IL302698A - Compounds and uses thereof - Google Patents

Compounds and uses thereof

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Publication number
IL302698A
IL302698A IL302698A IL30269823A IL302698A IL 302698 A IL302698 A IL 302698A IL 302698 A IL302698 A IL 302698A IL 30269823 A IL30269823 A IL 30269823A IL 302698 A IL302698 A IL 302698A
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cancer
compound
optionally substituted
pharmaceutically acceptable
acceptable salt
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IL302698A
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Hebrew (he)
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Foghorn Therapeutics Inc
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Publication of IL302698A publication Critical patent/IL302698A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

WO 2022/103899 PCT/US2021/058865 COMPOUNDS AND USES THEREOF Background The invention relates to compounds useful for modulating BRG1- or BRM-associated factors (BAF) complexes. In particular, the invention relates to compounds useful for treatment of disorders associated with BAF complex function.Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is a mechanism by which such gene expression occurs. The human Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, also known as BAF complex, has two SWI2-like ATPases known as BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcription activator BRG1, also known as ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancer tumors and is needed for cancer cell proliferation. BRM, also known as probable global transcription activator SNF2L2 and/or ATP-dependent chromatin remodeler SMARCA2, is encoded by the SMARCA2 gene on chromosome 9 and has been shown to be essential for tumor cell growth in cells characterized by loss of BRG1 function mutations. Deactivation of BRG and/or BRM results in downstream effects in cells, including ceil cycle arrest and tumor suppression.
Summary The present invention features compounds useful for modulating a BAF complex. In some embodiments, the compounds are useful for the treatment of disorders associated with an alteration in a BAF complex, eg., a disorder associated with an alteration in one or both of the BRG1 and BRM proteins. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating such disorders.In one aspect, the invention provides a compound having the structure: Formulawherem is Q, 1,2, or 3;n is 0, 1,2, 3, or 4;X1 is -S- -SO-, -SO2-, or -S(O)(NH)-;؛; X2 is N or CRR1 is hydrogen or optionally substituted C1-C6 alkyl;each R2 and each R3 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C؛-Cs heteroalkyl;L1 is optionally substituted 9- or 10-membered bicyclic heterocyclyl or optionally substituted 9- or 10-membered bicyclic heteroaryl; 1 WO 2022/103899 PCT/US2021/058865 L2 is absent, optionaiiy substituted C3-C10 cycloalkyl, optionally substituted Ce-C10 aryi, optionally substituted 5- to 14-membered heteroaryl, or optionally substituted 4- to 14-membered heterocydyl;R4 is hydrogen, halo, optionally substituted C؛-C5 alkyl, or optionally substituted C3-C10 cycloalkyl;R5 is optionally substituted C1-C8 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted amino, and R6 is hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted Cg-Co alkenyl, or optionally substituted C3-C10 cycloalkyl; or R5 and R6, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 8-membered heterocydyl;each R7 is independently optionally substituted C1-Ce alkyl, optionally substituted C1-Cs heteroalkyl, halo, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 cycloalkyl C1-Calkyl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocydyl, -N(R7A)2, or-OR 7A, wherein each R7A is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted Ce- Cw aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocydyl, or two geminal R7A groups, together with the atom to which they are attached, combine to form optionally substituted 5- to 10-membered heteroaryl or optionally substituted 4- to 10-membered heterocydyl; or two geminal R7 groups, together, with the atom to which they are attached, combine to form carbonyl;R8 is hydrogen, halo, optionally substituted C1-C5 alkyl, or optionally substituted C3-C10 cycloalkyl; andRs is hydrogen or halo;or a pharmaceutically acceptable salt thereof.In some embodiments, the variables for the compound of Formula I are as follows: m is 0,1,2, or 3;n is Q, 1,2, 3, or 4;X1 is S, SO, SO2, or S(O)(NH);X2 is N or CR8;R1 is hydrogen or optionally substituted C1-C6 alkyl;each R2 and each R3 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted Ci-Cs heteroalkyl;L1 is optionally substituted 9- or 10-membered bicyclic heterocydyl or optionally substituted 9- or 10-membered bicyclic heteroaryl;L2 is absent, optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocydyl;R4 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl;R5 is optionally substituted C!-Cs alkyl, optionally substituted C1-C8 heteroalkyl, or optionally substituted amino, and R® is hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl; or R5 and Rs , together with the atoms to which they are attached, combine to form an optionally substituted 5- to 8-membered heterocydyl;each R7 is independently optionally substituted C1-C6 alkyl, optionally substituted C1-Cheteroalkyl, halo, optionally substituted C:-C10 cycloalkyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered heterocydyl, -N(R7A)2, or-OR 7A, where each R7A is 2 WO 2022/103899 PCT/US2021/058865 independently H, optionally substituted C:-C5 alkyl, optionally substituted C؛-C5 heteroalkyl, optionally substituted C:-C10 cycloalkyl, optionally substituted C6-C:0 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R7A groups, together with the atom to which they are attached, combine to form optionally substituted 5- to 10-membered heteroaryl or optionally substituted 4- to 10-membered heterocyclyl;R8 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-Cw cycloalkyl;andR® is hydrogen;or a pharmaceutically acceptable salt thereof.In some embodiments, L2 is absent, optionally substituted C3-C10 cycloalkyl, optionally substituted Ce-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10- membered heterocyclyl.in some embodiments, each R7 is independently optionally substituted C1-C6 alkyl, optionally substituted C1-Cs heteroalkyl, halo, optionally substituted C3-C10 cycloalkyl, optionally substituted 5- to 10- membered heteroaryl, optionally substituted 4- to 10-membered heterocyclyl, -N(R7A)2, or-OR 7A, where each R7A is independently H, optionally substituted C1־Ce alkyl, optionally substituted C1-Ce heteroaikyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10- membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R7A groups, together with the atom to which they are attached, combine to form optionally substituted 5- to 10-membered heteroaryl or optionally substituted 4- to 10-membered heterocyclyl.In some embodiments, R5 and R®, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 8-membered heterocyclyl. In some embodiments, R5 and R®, together with the atoms to which they are attached, combine to form an optionally substituted 7-membered heterocyclyl.In some embodiments, R5 is optionally substituted C1-C8 alkyl. In some embodiments, R5 is optionally substituted amino. In some embodiments, R® is optionally substituted C:-C5 alkyl. In some embodiments, R® is halo.In some embodiments, X1 is SO2. In some embodiments, X2 is CR8.In some embodiments, is a group of the following structure whereZ is CH2, CO, or C(RX2)2;each RX1 is independently optionally substituted C1-C5 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl; 3 WO 2022/103899 PCT/US2021/058865 each Rx2 is independently H or optionally substituted C1-C6 alkyl; and p is 0, 1,2, 3, or 4.In some embodiments, /XiR5R6 is a group of the following structure (rX1WR4 R8 whereZ is CH2, CO, or C(RX2)2:each RX1 is independently optionally substituted C1-C6 alkyl or halo, or two geminal Rx! groups, together with the atom to which they are attached, combine to form a carbonyl;each Rx2 is independently H or optionally substituted C1-C6 alkyl; andp is 0, 1,2, 3, or 4.In some embodiments,R4 is a group of the following structure whereZ is CH2, CO, or C(RX2)2;each RX1 is independently optionally substituted C1-C6 alkyl or halo, or two geminal Rx ■ groups, together with the atom to which they are attached, combine to form a carbonyl;each Rx2 is independently hydrogen or optionally substituted C1-Ce alkyl:p is 0, 1,2, 3, or 4; andq is 0 or 1,In some embodiments,R4 is a group of the following structure 4 WO 2022/103899 PCT/US2021/058865 whereZ is CH2, CO, or C(RX2)2;each RX1 is independently optionally substituted C1-C6 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;each Rx2 is independently hydrogen or optionally substituted C1-C6 alkyl; andp is 0, 1,2, 3, or 4.In some embodiments,R4 is a group of the following structure Il is a single bond or double bond;each RX1 is independently optionally substituted C؛-C5 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;Rx2 is hydrogen or optionally substituted C1-C8 alkyl; andp is 0, 1,2, 3, or 4.In some embodiments,R4 is a group of the following structure R8 whereeach RX1 is independently optionally substituted C1-C5 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;Rx2 is hydrogen or optionally substituted C1-C8 alkyl; andp is 0, 1,2, 3, or 4. 5 WO 2022/103899 PCT/US2021/058865 In some embodiments, R8 is hydrogen.in some embodiments, R8 is halo.in some embodiments, R8 is optionaiSy substituted C3-Ce cycloalkyl.in some embodiments, X2 is N.in some embodiments, is a group of the foliowing structure whereZ is CH2, CO, or C(RX2)2;each RX1 is independently optionally substituted C1-Cs alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;each Rx2 is independently hydrogen or optionally substituted C1-C6 alkyl; andp is 0, 1,2, 3, or 4.in some embodiments, is a group of the following structure whereeach RX1 is independently optionally substituted C1-C6 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl or Cz-Ca cycloalkyl ring, or two vicinal RX1 groups, together with the atoms to which they are attached, combine to form C3-Ce cycloaikyl ring;p is 0, 1,2, 3, or 4; andq is 0, 1, or 2.In some embodiments, is a group of the following structure 6 WO 2022/103899 PCT/US2021/058865 whereeach RX1 is independently optionally substituted C1-C6 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl; andp is 0, 1,2, 3, or 4.In some embodiments, at least one RX1 is optionally substituted C1-C6 alkyl.In some embodiments, -L2-(R7)n is a group of the following structure:In some embodiments, at least one RX1 is halo.In some embodiments, at least two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl.In some embodiments, L؛ is optionally substituted 9- or 10-membered bicyclic heteroaryl.In some embodiments, L1 is Formula Awhereeach of X3, X4, X5, X6, X7, and Xs is independently N or CRL1;each RL1 is independently H, halo, optionally substituted C1-C6 alkyl;A1 is a bond to -(C(R2)(R3))m-; andA2 is a bond to L2.In some embodiments, L1 is In some embodiments, U is In some embodiments, L1 is In some embodiments, L1 is In some embodiments, L1 is 7 WO 2022/103899 PCT/US2021/058865 In some embodiments, L1 is whereA1 is a bond to ״(C(R2)(R3))m-; andA2 is a bond to L2.In some embodiments, L2 is optionally substituted 5- to 10-membered heteroaryl.In some embodiments, -L2-(R7)n is a group of the following structure: 8 WO 2022/103899 PCT/US2021/058865 9 WO 2022/103899 PCT/US2021/058865 In some embodiments, -L2-(R')n is a group of the foilowing structure: In some embodiments, -L2-(R')n is a group of the following structure: In some embodiments, -L2-(R7)n is a group of the following structure: 10In some embodiments, -^-(ROn is a group of the following structure: In some embodiments, -L2-(R')n is a group of the following structure: WO 2022/103899 PCT/US2021/058865 In some embodiments, -L2-(R')n is a group of the following structure: (R7)n , Sr , ,or N^N In some embodiments, -L2-(R7)n is a group of the following structure: In some embodiments, L2 is optionally substituted 06-Cw aryl.In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.In some embodiments, R7 is optionally substituted C1-C6 alkyl. In some embodiments, R7 is optionally substituted C1-C8 heteroalkyl. In some embodiments, R7 is optionally substituted 4- to 10- membered heterocyclyl. In some embodiments, R7 is optionally substituted azetidinyl or optionally substituted morpholinyl. In some embodiments, R7 is optionally substituted C3-C10 cycloalkyl. In some embodiments, R7 is optionally substituted cyclopropyl or optionally substituted cyclobutyl. In some embodiments, R7 is -N(R7A)2. In some embodiments, R7 is optionally substituted N-azetidinyl or optionally substituted N-morphohnyl. In some embodiments, two geminal R7 groups, together with the atom to which they are attached, combine to form optionally substituted 4- to 10-membered heterocyclyl. In some embodiments, at least one R7 is -OR7A. In some embodiments, R7A is optionally substituted C1-6 alkyl.In some embodiments, n is 0.In some embodiments, at least one R7 is cyclopropyl, 2,2-difluorocyclopropyl, difluoromethoxy, 2,6-dimethylmorpholin-4-yl, N-azetidinyl, 3-fluorocyclobutyl, 2-methoxyethyl, ethoxy, methoxy, 2,2- difluoroethoxy, 2,2-difluoroethyl, trifluoromethyl, isopropyl, methyl, acetyl, fluoro, chloro, 1-methylpyrazol- 3-yl, dimethylamino, N-methyl-N-(2-methoxyethyl)-amino, N-ethyl-N-(2-methoxyethyl)-amino, N-(2- propyl)-N-(2-methoxyethyl)-amino, 2-methoxyethylamino, 3-aza-8-oxa-bicyclo[4.3.0]non-3-yl, 3-aza-7- oxa-bicyclo[4.3.0]non-3-yl, 1-fluorocyclobut-1-yl, 3-fluoropyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, oxetan- 3-yl, N-methylindolin-4-yl, 2,2-difluoro-3-methylcycloprop-1-yl, 3-methoxyazetidin-l-yl, 3- methoxypiperidin-1-yl, 1,2-dimethyl-7-azaindol-4-yl, 1-methyl-7-azaindol-4-yl, 2,3-methylenedioxyphenyl, N-methyl-N-(3-oxetanyl)amino, 3-oxetanyloxy, 1,1-difluoro-5-azaspiro[2.3]hex-5-yl, 1-fluoromethyl- cyclopropyl, N-(3-tetrahydrofuranyl)methylamino, N-indolinyl, N-1,4-oxazepanyl, 2-fluoro-2-propyL 1,1- difluoro-2-propyl, 2,2-difluoro-1 -methylcycloprop- 1 -yl, 1-methylcyclopropyl, 4,4-difluoropiperidin-1-yl, 2- methoxyethoxy, 3,3-difluorocyclobut-1 -yl, N-methyl-N-1 -methoxyprop-2-ylamino, 1 -methoxyprop-2- ylamino, 1-methoxyethyl, 4-methylpiperazinyl, 3-methylmorpholinyl, 2,2-difluoropropoxy, 3- 11 WO 2022/103899 PCT/US2021/058865 methoxycyclobutyl, methylamino, 4-d!methylamino-3,3-dlfluoropiperid!nyl, 4-methylam!no-3,3- difluoropiperidiny I, 3,3-difluoropyrrohdinyl, N-methyl-N-3-methoxycyclobutylamino, 1 -methylpyrazol-5-yl, 6-oxa-3-azabicyclo[3.1.1jhept-3-yl, cyclopropyloxy, 2,6-dimethylpyrid-4-yl, 2-methylpyrrolidinyl, 4- oxabicydo[4.1.0]hept-1-yl, N-methyl-N-(2,6-dimethyltetrahydropyran-4-yl)amino, or N-methyl-N-3-methyloxetan-3-ylmethylamino.In some embodiments, R1 is hydrogen.In another aspect, the invention provides a compound selected from the group consisting of compounds 1-308 in Table 1A and pharmaceutically acceptable salts thereof. 12 WO 2022/103899 PCT/US2021/058865 13 WO 2022/103899 PCT/US2021/058865 14 WO 2022/103899 PCT/US2021/058865 WO 2022/103899 PCT/US2021/058865 16 WO 2022/103899 PCT/US2021/058865 17 WO 2022/103899 PCT/US2021/058865 18 WO 2022/103899 PCT/US2021/058865 19 WO 2022/103899 PCT/US2021/058865 WO 2022/103899 PCT/US2021/058865 21 WO 2022/103899 PCT/US2021/058865 22 WO 2022/103899 PCT/US2021/058865 23 WO 2022/103899 PCT/US2021/058865 24 WO 2022/103899 PCT/US2021/058865 WO 2022/103899 PCT/US2021/058865 26 WO 2022/103899 PCT/US2021/058865 27 WO 2022/103899 PCT/US2021/058865 28 WO 2022/103899 PCT/US2021/058865 29 WO 2022/103899 PCT/US2021/058865 WO 2022/103899 PCT/US2021/058865 31 WO 2022/103899 PCT/US2021/058865 32 WO 2022/103899 PCT/US2021/058865 33 WO 2022/103899 PCT/US2021/058865 34 WO 2022/103899 PCT/US2021/058865 WO 2022/103899 PCT/US2021/058865 36 WO 2022/103899 PCT/US2021/058865 37 WO 2022/103899 PCT/US2021/058865 38 WO 2022/103899 PCT/US2021/058865 39 WO 2022/103899 PCT/US2021/058865 40 WO 2022/103899 PCT/US2021/058865 41 WO 2022/103899 PCT/US2021/058865 42 WO 2022/103899 PCT/US2021/058865 43 WO 2022/103899 PCT/US2021/058865 44 WO 2022/103899 PCT/US2021/058865 45 WO 2022/103899 PCT/US2021/058865 46 WO 2022/103899 PCT/US2021/058865 47 WO 2022/103899 PCT/US2021/058865 48 WO 2022/103899 PCT/US2021/058865 49 WO 2022/103899 PCT/US2021/058865 50 WO 2022/103899 PCT/US2021/058865 51 WO 2022/103899 PCT/US2021/058865 52 WO 2022/103899 PCT/US2021/058865 53 WO 2022/103899 PCT/US2021/058865 54 WO 2022/103899 PCT/US2021/058865 55 WO 2022/103899 PCT/US2021/058865 56 WO 2022/103899 PCT/US2021/058865 57 WO 2022/103899 PCT/US2021/058865 58 WO 2022/103899 PCT/US2021/058865 59 WO 2022/103899 PCT/US2021/058865 60 WO 2022/103899 PCT/US2021/058865 61 WO 2022/103899 PCT/US2021/058865 62 WO 2022/103899 PCT/US2021/058865 63 WO 2022/103899 PCT/US2021/058865 64 WO 2022/103899 PCT/US2021/058865 65 WO 2022/103899 PCT/US2021/058865 66 WO 2022/103899 PCT/US2021/058865 67 WO 2022/103899 PCT/US2021/058865 68 WO 2022/103899 PCT/US2021/058865 69 WO 2022/103899 PCT/US2021/058865 70 WO 2022/103899 PCT/US2021/058865 In another aspect, the invention provides a compound selected from the group consisting of compounds 309-856 in Table 1B and pharmaceutically acceptable salts thereof.
Table IB. Compounds of the Invention (cyclic and acyclic sulfones) 71 WO 2022/103899 PCT/US2021/058865 72 WO 2022/103899 PCT/US2021/058865 73 WO 2022/103899 PCT/US2021/058865 Compound # Structure 331 9/P 9 AfiZ § N 'AXA' VX 1 J H J J J V ovV 332 I X ■ zm v O© 333 £O V / z ״x ^ □ = = /A o-'-p ןV_/O 334 ^p 0 AA- n ~N ؟، N /Xpv n ־ A LiU H mJ a X^o״^ 335 F , Uf9/P 9 fA| F /° H NAlX ،״ O~P 336 /ץ 0 0 0 *?.״ VJJ H nAx a 337 9/p 9 ן y.--־S. x؟s. xA ./Pv N. /"X / / MyBN8 ־V N NVXJ " A 338 Ai N A J UQ - IX- a 339 A0 9 fA!0Me ״ Xp H XXA Q ؟ F 340 aO ^ D ' x U " F = V J / ־ A o=، ) ox ) ^ x Ox /A/O 74 WO 2022/103899 PCT/US2021/058865 Compound # Structure 341 a . p- U - ^z.x o pY ،؛ 342 / ז _ J bY b p O _ O O p ) 343 o ^ p (Y p 1 ״ oX J p O ^ ، y C / X _ C h - - ^ ­ ח ­דו 1 344 9/0 9 YY!z־״S. ,/•x Yx zx ,/x /Nx /x- Y /x. C Y1 h bfv yx fr -P^ -.,Jy 345 yy ؟ 9 > °,—'S. zx /L /X /X ،N، /X- /*X n C u BllF t o 346 ס-!,/ j % p o p f ־ X/־ ־ ־ ־ ־ ־ ־ x ° ן ) ס"^x/O 347 // O o / ״ n w ״ ° z b O ( ZT O=/ S Q 348 T 1 ץ/ 1 -Ot i— V = / x o p o p Q m P ^ V m 349 9/P 0 A / YYy h ך ך N y o—/ Y/Ox 350 9/0 0 Y> / 11 ך M Y 11o^/PY nPV YYP 75 WO 2022/103899 PCT/US2021/058865 76 WO 2022/103899 PCT/US2021/058865 77 WO 2022/103899 PCT/US2021/058865 Compound # Structure 370 / L - o x o xz o o r f - o־ 371 —o p— o==، y v ° ' 3 372 " y Q o y=z: o pH O ,. / ؛ b c O ״O ' > i 373 V 8 n 33 3F r yyyyyy yk n k/ 374 ס־^^ץr v < ° < O V J y ־ x ,—, z. > b 375 v0 a 376 p X z ^™ ־. z xO=X ، — / C C O ) ״ — / 1 ' O_ / V 377 k3M H L/0 378 Hi ] ؟ °-? 1 n r : !؛ r N ؟ 9 /؛ . I ؛؛ J h ע 379 yy ־ 0 vp ؟r"s x/Xx Jk / -N- Jx.Y r n ؛ N T ח /؛ b-Jv A- U 380 yy ؟ vp ؟r״sx/^A /x/Xz Nx/ N wk״״ h jfr t y N !ג } Q-VW N^x^ -N 78 WO 2022/103899 PCT/US2021/058865 WO 2022/103899 PCT/US2021/058865 80 WO 2022/103899 PCT/US2021/058865 81 WO 2022/103899 PCT/US2021/058865 82 WO 2022/103899 PCT/US2021/058865 Compound # Structure 421 z ؟ p °- / Y I NYMV ,NAO-YxY -_ ) 422 a 9 n~ n A ؟ y n yYAx / aJ h n aa v F 423 v0 9 All ؟ ׳׳''/8־״x/^xA N. A/ BNJ J V ؛ 1 J H A* v^P N .ay 424 ( P P ־ p o m V AY=o x * z .
A X . . / Z A 425 o ؟ Y A A o :2 : 426 / ....( O X - ( 7 z A f 3°s / A/ ؛؟ o 427 L LX o/™־־ A / A> ( ־ ־ 2 :3 : o A o x A O'. /A / ° 428 Ap 9 O1 a/-s(/xxA AN N י؟ f YNo-.A^P ^xaAy' Pa 429 9/0 o YA bAx H nAy A 430 ?.,,0 0 ar^^vA 0AY H nv^1 0^ v 83 WO 2022/103899 PCT/US2021/058865 84 WO 2022/103899 PCT/US2021/058865 85 WO 2022/103899 PCT/US2021/058865 86 WO 2022/103899 PCT/US2021/058865 87 WO 2022/103899 PCT/US2021/058865 88 wo 2022/103899 PCTS2O21/O58865 89 WO 2022/103899 PCT/US2021/058865 90 WO 2022/103899 PCT/US2021/058865 91 WO 2022/103899 PCT/US2021/058865 92 WO 2022/103899 PCT/US2021/058865 93 WO 2022/103899 PCT/US2021/058865 94 WO 2022/103899 PCT/US2021/058865 95 WO 2022/103899 PCT/US2021/058865 96 WO 2022/103899 PCT/US2021/058865 97 WO 2022/103899 PCT/US2021/058865 98 WO 2022/103899 PCT/US2021/058865 99 WO 2022/103899 PCT/US2021/058865 100 WO 2022/103899 PCT/US2021/058865 101 WO 2022/103899 PCT/US2021/058865 102 103 W O 2022/103899 PCT/US2021/058865 WO 2022/103899 PCT/US2021/058865 104 WO 2022/103899 PCT/US2021/058865 105 WO 2022/103899 PCT/US2021/058865 106 WO 2022/103899 PCT/US2021/058865 107 WO 2022/103899 PCT/US2021/058865 Compound # Structure 594 Oq 0 chf2 595 ، H * H 1 1 1 596 ■/י . X ' ؛ ■י■ -'־י^-^. X ■'''׳ ■ - vX ^ VJ 597 ■'׳xxy״A(י 598 V ii .. O נ !י 1 r t ؛ Y1 ) AwwwwS■ 108 WO 2022/103899 PCT/US2021/058865 109 WO 2022/103899 PCT/US2021/058865 110 WO 2022/103899 PCT/US2021/058865 111 WO 2022/103899 PCT/US2021/058865 112 WO 2022/103899 PCT/US2021/058865 113 WO 2022/103899 PCT/US2021/058865 114 WO 2022/103899 PCT/US2021/058865 115 WO 2022/103899 PCT/US2021/058865 116 WO 2022/103899 PCT/US2021/058865 117 WO 2022/103899 PCT/US2021/058865 118 WO 2022/103899 PCT/US2021/058865 119 WO 2022/103899 PCT/US2021/058865 120 WO 2022/103899 PCT/US2021/058865 121 122 W O 2022/103899 PCT/US2021/058865 WO 2022/103899 PCT/US2021/058865 123 WO 2022/103899 PCT/US2021/058865 124 WO 2022/103899 PCT/US2021/058865 125 WO 2022/103899 PCT/US2021/058865 126 WO 2022/103899 PCT/US2021/058865 127 WO 2022/103899 PCT/US2021/058865 128 WO 2022/103899 PCT/US2021/058865 129 WO 2022/103899 PCT/US2021/058865 130 WO 2022/103899 PCT/US2021/058865 131 WO 2022/103899 PCT/US2021/058865 132 WO 2022/103899 PCT/US2021/058865 133 WO 2022/103899 PCT/US2021/058865 134 WO 2022/103899 PCT/US2021/058865 135 WO 2022/103899 PCT/US2021/058865 136 WO 2022/103899 PCT/US2021/058865 137 WO 2022/103899 PCT/US2021/058865 138 WO 2022/103899 PCT/US2021/058865 139 WO 2022/103899 PCT/US2021/058865 140 WO 2022/103899 PCT/US2021/058865 141 WO 2022/103899 PCT/US2021/058865 142 WO 2022/103899 PCT/US2021/058865 143 WO 2022/103899 PCT/US2021/058865 144 WO 2022/103899 PCT/US2021/058865 145 WO 2022/103899 PCT/US2021/058865 146 WO 2022/103899 PCT/US2021/058865 147 In some embodiments, the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 5. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM ICs0 of at least 7. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM ICs0 of at least 10. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 15. In some embodiments, the compound has a ratio of BRG1 ICs0 to BRM IC5c• of at least 20. In some embodiments, the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 25. In some embodiments, the compound has a ratio of BRG1 ICs0 to BRM IC50 of at least 30.In another aspect, the invention features a pharmaceutical composition including any one of the above compounds and a pharmaceutically acceptable excipient.In another aspect, the invention features a method of decreasing the activity of a BAF complex in a cell, the method involving contacting the cell with an effective amount of any of the foregoingcompounds or a pharmaceutical composition thereof. 148 WO 2022/103899 PCT/US2021/058865 In some embodiments, the cell is a cancer cell.In another aspect, the invention features a method of treating a BAF complex-related disorder in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.In some embodiments, the BAF complex-related disorder is cancer.In a further aspect, the invention features a method of inhibiting BRM, the method involving contacting a cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.In another aspect, the invention features a method of inhibiting BRG1, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.In a further aspect, the invention features a method of inhibiting BRM and BRG1, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.In another aspect, the invention features a method of treating a disorder related to a BRG1 loss of function mutation in a subject in need thereof, the method involving administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.In some embodiments, the disorder related to a BRG1 loss of function mutation is cancer. In other embodiments, the subject is determined to have a BRG1 loss of function disorder, for example, is determined to have a BRG1 loss of function cancer (for example, the cancer has been determined to include cancer cells with loss of BRG1 function).In another aspect, the invention features a method of inducing apoptosis in a cell, the method involving contacting the cell with an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof. In some embodiments, the cell is a cancer cell.In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or a pharmaceutical composition thereof.In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non- melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic, tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non- melanoma skin cancer, endometrial cancer, or penile cancer.In some embodiments of any of the foregoing methods, the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., vemurafenib, dacarbazine, a CTLA4 inhibitor, a PDinhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, perjeta, tamoxifen, xeloda, docetaxol, platinum agents such as carboplatin, 149 WO 2022/103899 PCT/US2021/058865 taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inihibitors, alimta, abraxane, Adriamycin®, gemcitabine, avastin, halaven, neratinib, a PARP inhibitor, ARN810, an mTOR inhibitor, topotecan, gemzar, a VEGFR2 inhibitor, a folate receptor antagonist, demcizumab, fosbretabulin, ora PDLinhibitor).in some embodiments of any of the foregoing methods, the cancer has or has been determined to have BRG1 mutations, in some embodiments of any of the foregoing methods, the BRG1 mutations are homozygous, in some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the foregoing methods, the cancer does not have, or has been determined not to have, an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the foregoing methods, the cancer has, or has been determined to have, a KRAS mutation. In some embodiments of any of the foregoing methods, the BRG1 mutation is in the ATPase catalytic domain of the protein, in some embodiments of any of the foregoing methods, the BRG1 mutation is a deletion at the C-terminus of BRG1.In another aspect, the disclosure provides a method treating a disorder related to BAF (e.g., cancer or viral infections) in a subject in need thereof. This method includes contacting a cell with an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the disorder is a viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus (HSV-2), human herpesvirus 6 (HHV-6), Herpesvitus K*, CMV, varicella-zoster virus), Papillomaviridae family (e.g., Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), Togaviridae family (e.g., Rubella virus). In some embodiments, the disorder is Coffin Siris, Neurofibromatosis (e.g., NF-1, NF-2, or Schwannomatosis), or Multiple Meningioma.In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof. This method includes administering to the subject an effective amount of any of the foregoing compounds, or pharmaceutically acceptable salts thereof, or any of the foregoing pharmaceutical compositions. In some embodiments, the viral infection is an infection with a virus of the Retroviridae family such as the lentiviruses (e.g., Human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T cell leukemia virus I (HTLV-I), human T ceil leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., Human Adenovirus), Herpesviridae family (e.g., Human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), Herpesvitus K*, CMV, varicella-zoster virus), Papillomaviridae family (e.g., Human Papillomavirus (HPV, HPV E1)), Parvoviridae family (e.g., Parvovirus B19), Polyomaviridae family (e.g., JC virus and BK virus), Paramyxoviridae family (e.g., Measles virus), or Togaviridae family (e.g., Rubella virus). 150 WO 2022/103899 PCT/US2021/058865 In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.In another aspect, the invention features a method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method including administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.In another aspect, the invention features a method of suppressing metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.In another aspect, the invention features a method of suppressing metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method including administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.In another aspect, the invention features a method of reducing the level and/or activity of BRGand/or BRM in a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer cell, the method including contacting the cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cell is in a subject.In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and/or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of BRG1 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference, in some embodiments, the effective amount of the compound that reduces the level and/or activity of BRG1 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).In some embodiments, the effective amount of the compound reduces the level and/or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference feral least 12 hours (e.g., hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the compound that reduces the level and/or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).In some embodiments of any of the above aspects, the effective amount of the compound reduces the level and/or activity of BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or 151 WO 2022/103899 PCT/US2021/058865 activity of BRM by at least 50% (e g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference. In some embodiments, the effective amount of the compound that reduces the level and/or activity of BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 9/%, 98%, or 99%).In some embodiments, the effective amount of the compound reduces the level and/or activity of BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least 12 hours (e.g., hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, or more). In some embodiments, the effective amount of the compound that reduces the level and/or activity of BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) as compared to a reference for at least days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and/or BRM protein and/or the cell or subject has been identified as expressing BRG1 and/or BRM. In some embodiments, the cancer expresses BRG1 protein and/or the cell or subject has been identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein and/or the cell or subject has been identified as expressing BRM. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematologic cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the cancer is breast cancer (e.g., an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer). In some embodiments, the cancer is a bone cancer (e.g., Ewing ’s sarcoma). In some embodiments, the cancer is a renal cell carcinoma (e.g., a Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). The metastatic cancer can include cells exhibiting migration and/or invasion of migrating cells and/or include cells exhibiting endothelial recruitment and/or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer. In still other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. The metastatic cancer can be a cancer spread via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. Alternatively, the metastatic cancer can be a cancer spread via the lymphatic system, or a cancer spread hematogenously. In some embodiments, the effective amount of a compound of the invention is an amount effective to inhibit metastatic colonization of the cancer to the liver.In some embodiments the cancer harbors a mutation in GNAQ. In some embodiments the cancer harbors a mutation in GNA11. In some embodiments the cancer harbors a mutation in PLCB4. In some embodiments the cancer harbors a mutation in CYSLTR2. In some embodiments the cancer harbors a mutation in BAP1. In some embodiments the cancer harbors a mutation in SF3B1. In some embodiments the cancer harbors a mutation in EIF1 AX. In some embodiments the cancer harbors a TFE3 translocation. In some embodiments the cancer harbors a TFEB translocation. In some embodiments the cancer harbors a MITF translocation. In some embodiments the cancer harbors an 152 WO 2022/103899 PCT/US2021/058865 EZH2 mutation. In some embodiments the cancer harbors a SUZI2 mutation. In some embodiments the cancer harbors an EED mutation.In some embodiments of any of the foregoing methods, the method further includes administering to the subject or contacting the cell with an anticancer therapy, e.g., a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, ora combination thereof. In some embodiments, the anticancer therapy is a chemotherapeutic or cytotoxic, agent, e.g., an antimetabolite, antimitotic, antitumor antibiotic, asparagine-specific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor, ora combination thereof.In some embodiments of any of the foregoing methods, the compound of the invention is used in combination with another anti-cancer therapy used for the treatment of uveal melanoma such as surgery, a MEK inhibitor, and/or a PKC inhibitor. For example, in some embodiments, the method further includes performing surgery prior to, subsequent to, or at the same time as administration of the compound of the invention. In some embodiments, the method further includes administration of a MEK inhibitor and/or a PKC inhibitor prior to, subsequent to, or at the same time as administration of the compound of the invention.In some embodiments, the anticancer therapy and the compound of the invention are administered within 28 days of each other and each in an amount that together are effective to treat the subject.In some embodiments, the subject or cancer has and/or has been identified as having a BRGloss of function mutation.In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to chemotherapeutic or cytotoxic agents such as by genetic markers, or is likely to be resistant, to chemotherapeutic or cytotoxic agents such as a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent), in some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is resistant or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., Nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, ortametinib), and/or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).In some embodiments, the cancer is resistant to or failed to respond to a previously administered therapeutic used for the treatment of uveal melanoma such as a MEK inhibitor or PKC inhibitor. For example, in some embodiments, the cancer is resistant to or failed to respond to a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, ortametinib), and/or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196). 153 WO 2022/103899 PCT/US2021/058865 Chemical TermsThe terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as H atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.The term "acyl, " as used herein, represents a H or an alkyl group that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 11, or from 1 to 21 carbons.The term "alkenyl, " as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, or 2 to 6 carbon atoms). An alkenyl may be, e.g., monovalent or multivalent. One of skill in the art will recognize the number of applicable valencies from the context.The term "alkyl, " as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, to 6 carbon atoms, or 1 to 3 carbon atoms). An alkyl may be, e.g., monovalent or multivalent. One of skill in the art will recognize the number of applicable valencies from the context..The term "amino, " as used herein, represents ~N(RN1)2, where each RN1 is, independently, H, OH, NO2, N(Rn2)2, SO2ORn2, SO2Rn2, SORn2, an /V-protecting group, alkyl, alkoxy, aryl, arylaikyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), heteroaryl, or heterocyclyl, where each of these recited RN1 groups can be optionally substituted; or two RN1, together with the atom to which they are attached, combine to form a heterocyclyl or heteroaryl, and where each RN2 is, independently, H, alkyl, or aryl. The amino groups of the invention can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., --N(RN1)2).The term "aryl, " as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl. An aryl may be, e.g., monovalent or multivalent. One of skill in the art will recognize the number of applicable valencies from the context.The term "arylalkyl, " as used herein, represents an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to carbons, such as 01-Cb alkyl C6-C10 aryl, C1-C10 alkyl C6-C10 aryl, or C1-C20 alkyl C6-C10 aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each can be further substituted with 1,2, 3, or 4 substituent groups as defined herein for the respective groups.The term "azido, " as used herein, represents a -N3 group. 154 WO 2022/103899 PCT/US2021/058865 The term "bridged polycycloalkyl, " as used herein, refers to a bridged polycyclic group of 5 to carbons, containing from 1 to 3 bridges.The term "cyano, " as used herein, represents a -CN group.The term "carbocydyl, " as used herein, refers to a non-aromatic C3-C12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocydyl structures include cycloalkyl groups and unsaturated carbocydyl radicals.The term "cycloalkyl, " as used herein, refers to a saturated, non-aromatic, mono- or polycarbocyclic radical of 3 to 10, preferably 3 to 6 carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyi, and adamantyi. A cycloalkyl may be, e.g., monovalent or multivalent. One of skill in the art will recognize the number of applicable valencies from the context.The term "halo, " as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.The term "heteroalkyl, " as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1,2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an "alkoxy " which, as used herein, refers alkyl-O ״ (e.g., methoxy and ethoxy). A heteroalkyl may be, e.g., monovalent or multivalent. One of skill in the art will recognize the number of applicable valencies from the context.The term "heteroaryl, " as used herein, refers to a mono- or polycyclic radical of 5 to 14 (e.g., 5 to or 5 to 10) atoms having at least one aromatic ring and containing 1,2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. In some embodiments, a heteroaryl is C1-C9 heteroaryl (e.g., C2-Cg heteroaryl). One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxazolyl, thiazolyl, benzomorpholinyl, benzopiperidinyl, and indolinyL A heteroaryl may be, e.g., monovalent or multivalent. One of skill in the art will recognize the number of applicable valencies from the context.The term "heteroarylalkyl, " as used herein, represents an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ca-C9 heteroaryl C؛-Cs alkyl, C2-Cg heteroaryl C1-C10 alkyl, or C2-Cheteroaryl C1-C20 alkyl). In some embodiments, the alkyl and the heteroaryl each can be further substituted with 1,2,3, or 4 substituent groups as defined herein for the respective groups.The term "heterocyclyl, " as used herein, refers a mono- or polycyclic radical having 3 to 14 (e.g., to 12) atoms having at least one ring containing 1,2,3, or 4 ring atoms selected from N, O or S, where no ring is aromatic. In some embodiments, a heterocyclyl is a C2-C9 heterocyclyl. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyL pyranyl, pyrrolidinyl, tetrahydropyranyl, tetra hydrofuranyl, 1,3-dioxanyl, aza-oxybicyclo[4.3.0]nonyl, and aza-oxybicyclo[4.4.0]decyl,. A heterocyclyl may be, e.g., monovalent or multivalent. One of skill in the art will recognize the number of applicable valencies from the context.The term "heterocyclylalkyl, " as used herein, represents an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C2-Ce heterocyclyl C1-C6 alkyl, C2-C9 heterocyclyl C1-C 155 WO 2022/103899 PCT/US2021/058865 alkyl, or C2-Cs heterocyclyl C1-C20 alkyl). In some embodiments, the alkyl and the heterocyclyl each can be further substituted with 1,2, 3, or 4 substituent groups as defined herein for the respective groups.The term "hydroxyalkyl, " as used herein, represents alkyl group substituted with an -OH group. The term "hydroxyl," as used herein, represents an -OH group.The term "/V-protecting group, " as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis, " 3rd Edition (John Wiley & Sons, New York, 1999). /V-protecting groups include, but are not limited to, acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyL 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyL a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L, or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyL 2-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro4,5 ״-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1 -methylethoxycarbonyl, a,a-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl. Preferred /V-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t- butyloxycarbonyl (Boo), and benzyloxycarbonyl (Cbz).The term "nitro, " as used herein, represents an -NO2 group.The term "thiol, " as used herein, represents an -SH group.The alkyl, heteroalkyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified. Substituents include, for example: alkyl (e.g., unsubstituted and substituted, where the substituents include any group described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol. Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs 156 WO 2022/103899 PCT/US2021/058865 of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon. The appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art. "Racemate" or "racemic mixture" means a compound containing two enantiomers, where such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light. "Geometric isomer " means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) orZ (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis, " and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow forthe isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by mole fraction pure. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. 157 WO 2022/103899 PCT/US2021/058865 Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. "Isotopes " refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopicaliy enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 150, 170, 18q, 32p_ 33p35 ؛S, 18p ; 360^ 123g ane g 125ן Isotopically-labeled compounds (e.g., those labeled with 3H and 14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-(i.e., 14C) isotopes can be useful fortheir ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by 13C- or 14C-enriched carbon. Positron emitting isotopes such as 150, 13N, 11C, and 1SF are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopicaliy labelled compounds are known to those of skill in the art. For example, isotopicaliy labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopicaliy labeled reagent for a non-isotopically labeled reagent.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. 158 WO 2022/103899 PCT/US2021/058865 DefinitionsIn this application, unless otherwise clear from context, (i) the term "a" may be understood to mean "at least one "; (II) the term "or " may be understood to mean "and/or"; and (iii) the terms "including" and "including" may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps.As used herein, the terms "about " and "approximately " refer to a value that is within 10% above or below the value being described. For example, the term "about 5 nM " indicates a range of from 4.5 to 5.nM.As used herein, the term "administration " refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) may be by any appropriate route. For example, in some embodiments, administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumoral, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and vitreal.As used herein, the term "BAF complex " refers to the BRG1- or HBRM-associated factors complex in a human cell.As used herein, the term "BAF complex-related disorder " refers to a disorder that is caused or affected by the level of activity of a BAF complex.As used herein, the term "BRG1 loss of function mutation " refers to a mutation in BRG1 that leads to the protein having diminished activity (e.g., at least 1% reduction in BRG1 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity). Exemplary BRG1 loss of function mutations include, but are not limited to, a homozygous BRG1 mutation and a deletion at the C-terminus of BRG1.As used herein, the term "BRG1 loss of function disorder" refers to a disorder (e.g., cancer) that exhibits a reduction in BRG1 activity (e.g., at least 1% reduction in BRG1 activity, for example 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity).The term "cancer " refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.As used herein, a "combination therapy " or "administered in combination " means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap. In some embodiments, the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-formulated. In some embodiments, the two or more agents are not co-formulated and are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, 159 WO 2022/103899 PCT/US2021/058865 but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.By "determining the level " of a protein or RNA is meant the detection of a protein or an RNA, by methods known in the art, either directly or indirectly. "Directly determining " means performing a process (e.g., performing an assay or test on a sample or "analyzing a sample " as that term is defined herein) to obtain the physical entity or value. "Indirectly determining" refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value). Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners. Methods to measure RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analyses.By a "decreased level " or an "increased level " of a protein or RNA is meant a decrease or increase, respectively, in a protein or RNA level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, or less; or an increase by more than about 1.2-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0- fold, about 3.0-fold, about 3.5-fold, about 4.5-fold, about 5.0-fold, about 10-fold, about 15-fold, about 20- fold, about 30-fold, about 40-fold, about 50-fold, about 100-fold, about 1000-fold, or more). A level of a protein may be expressed in mass/vol (e.g., g/dL, mg/mL, pg/mL, ng/mL) or percentage relative to total protein in a sample.By "decreasing the activity of a BAF complex " is meant decreasing the level of an activity related to a BAF complex, or a related downstream effect. A non-limiting example of decreasing an activity of a BAF complex is Sox2 activation. The activity level of a BAF complex may be measured using any method known in the art, e.g., the methods described in Kadoch et al. Cell, 2013, 153, 71-85, the methods at which are herein incorporated by reference.As used herein, the term "inhibiting BRM" refers to blocking or reducing the level or activity of the ATPase catalytic binding domain or the bromodomain of the protein. BRM inhibition may be determined using methods known in the art, e g., a BRM ATPase assay, a Nano DSF assay, or a BRM Luciferase cell assay. 160 WO 2022/103899 PCT/US2021/058865 As used herein, the term "LXS196," also known as IDE196, refers to the PKC inhibitor having the structure: or a pharmaceutically acceptable salt thereof.The term "pharmaceutical composition," as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient and appropriate for administration to a mammal, for example a human. Typically, a pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.A "pharmaceutically acceptable excipient, " as used herein, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration.As used herein, the term "pharmaceutically acceptable salt " means any pharmaceutically acceptable salt of a compound, for example, any compound of Formula I. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid.The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are 161 WO 2022/103899 PCT/US2021/058865 well-known in the art. Saits may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.By a "reference " is meant any useful reference used to compare protein or RNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A "reference sample " can be, for example, a control, e.g., a predetermined negative control value such as a "normal control " or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound of the invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein or RNA (e.g., any described herein) at a known normal concentration. By "reference standard or level " is meant a value or number derived from a reference sample. A "normal control value " is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("between X and Y"), a high threshold ("no higher than X"), or a low threshold ("no lower than X"). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as "within normal limits " for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein or RNA, e.g., any described herein, within the normal reference range can also be used as a reference.As used herein, the term "subject " refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.As used herein, the terms "treat," "treated, ‘1 or "treating" mean therapeutic treatment or any measures whose object is to slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total); an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Compounds of the invention may also be used to "prophylactically treat " or "prevent " a disorder, for example, in a subject at increased risk of developing the disorder.As used herein, the terms "variant " and "derivative " are used interchangeably and refer to naturally-occurring, synthetic, and semi-synthetic analogues of a compound, peptide, protein, or other 162 WO 2022/103899 PCT/US2021/058865 substance described herein. A variant or derivative of a compound, peptide, protein, or other substance described herein may retain or improve upon the bioiogicai activity of the original material.The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
Brief Description of the Drawings FIG. 1 is a graph illustrating inhibition of cell proliferation of several cancer cell lines by a BRG1/BRM inhibitor (Compound A). FIG. 2Ais a graph illustrating inhibition of cell proliferation of uveal melanoma cell line 92-1 by a BRG1/BRM inhibitor (Compound A), a MEK inhibitor (Selumetinib), and a PKC inhibitor (LXS196). FIG. 2B is a graph illustrating inhibition of cell proliferation of uveal melanoma cell line MP41 by a BRG1/BRM inhibitor (Compound A), a MEK inhibitor (Selumetinib), and a PKC inhibitor (LXS196).FIG. 3 is a graph illustrating inhibition of cell proliferation of several cancer cell lines by a BRG1/BRM inhibitor (Compound B).FIG. 4 is a graph illustrating the area under the curves (AUCs) calculated from dose-response curves for cancer cell lines treated with a BRG1/BRM inhibitor.FIG. 5 is a graph illustrating inhibition of cell proliferation of uveal melanoma and non-small cell lung cancer cell lines by a BRG1/BRM inhibitor (Compound B).FIG. GA is a graph illustrating inhibition of cell proliferation of uveal melanoma cell line 92-1 by a BRG1/BRM inhibitor (Compound B), a MEK inhibitor (Selumetinib), and a PKC inhibitor (LXS196).FIG. 6B is a graph illustrating inhibition of cell proliferation of uveal melanoma cell line MP41 by a BRG1/BRM inhibitor (Compound B), a MEK inhibitor (Selumetinib), and a PKC inhibitor (LXS196).FIG. 7A is a graph illustrating inhibition of cell proliferation of parental and PKC-inhibitor refractory uveal melanoma cell lines by a PKC inhibitor (LXS196).FIG. 7B is a graph illustrating inhibition of cell proliferation of parental and PKC-inhibitor refractory uveal melanoma cell lines by a BRG1/BRM inhibitor (Compound B).FIG. 8Ais a graph illustrating inhibition of tumor growth in mice engrafted with uveal melanoma cell lines by a BRG1/BRM inhibitor (Compound C).FIG. 8B is an illustration of the size of tumors from mice engrafted with uveal melanoma cell lines and dosed with a BRG1/BRM inhibitor (Compound C).FIG. 8C is a graph illustrating body weight change of mice engrafted with uveal melanoma cell lines and dosed with a BRG1/BRM inhibitor (Compound C).
Detailed Description The present disclosure features compounds useful for the inhibition of BRM and optionally BRG1. These compounds may be used to modulate the activity of a BAF complex, for example, for the treatment of a BAF-related disorder, such as cancer (e.g., BRG1-loss of function disorders). Exemplary compounds described herein include compounds having a structure according to FormulaI: 163 WO 2022/103899 PCT/US2021/058865 Formula I wherem is 0, 1,2, or 3;n is 0, 1,2, 3, or 4;X1 is -S-, -SO-, -SO2-, or -S(O)(NH)-;X2 is N or CR8;R1 is hydrogen or optiona^y substituted C1-C6 alkyl;each R2 and each R3 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C؛-Cs heteroalkyl;L1 is optionally substituted 9- or 10-membered bicyclic heterocyclyl or optionally substituted 9- or 10-membered bicyclic heteroaryl;L2 is absent, optionally substituted C3-C10 cycloalkyl, optionally substituted 06-Cw aryl, optionally substituted 5- to 14-membered heteroaryl, or optionally substituted 4- to 14-membered heterocyclyl:R4 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycioalkyl;R5 is optionally substituted C1-C8 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted amino, and R8 is hydrogen, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-Cs alkenyl, or optionally substituted C:-C10 cycloalkyl; or R5 and R®, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 8-membered heterocyclyl;each R7 is independently optionally substituted C1-C8 alkyl, optionally substituted C1-Cheteroalkyl, halo, optionally substituted C3-C1 cycloalkyl, optionally substituted C3-C10 cycloalkyl C1-Calkyl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyclyl, -N(R7A)2, or-OR 7A, wherein each R7A is independently H, optionally substituted C1-C6 alkyl, optionally substituted C:-C5 heteroalkyl, optionally substituted C3-C10 cycioalkyl, optionally substituted C6- C!o aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyclyl, or two geminal R7A groups, together with the atom to which they are attached, combine to form optionally substituted 5- to 10-membered heteroaryl or optionally substituted 4- to 10-membered heterocyclyl; or two geminal R7 groups, together, with the atom to which they are attached, combine to form carbonyl;R8 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycioalkyl; andR9 is hydrogen or halo;or a pharmaceutically acceptable salt thereof.In some embodiments, the compound, or pharmaceutically acceptable salt thereof, has the structure of any one of compounds 1-308 in Table 1A. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, has the structure of any one of compounds 309-856 in Table 1B. 164 WO 2022/103899 PCT/US2021/058865 Other embodiments, as well as exemplary methods for the synthesis of production of these compounds, are described herein.
Pharmaceutical Uses The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their ability to modulate the level, status, and/or activity of a BAF complex, i.e., by inhibiting the activity of the BRG1 and/or BRM proteins within the BAF complex in a mammal. BAF complex-related disorders include, but are not limited to, BRG1 loss of function mutation-related disorders.An aspect of the present invention relates to methods of treating disorders related to BRG1 loss of function mutations such as cancer (e.g., non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer) in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of: (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, (i) increased progression free survival of subject.Treating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. For example, the size of a tumor may be measured as a diameter of the tumor.Treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. For example, the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating fora population the average length of survival following initiation of treatment with the compound of the invention. An increase in average survival time of a population may also be measured, 165 WO 2022/103899 PCT/US2021/058865 for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.Exemplary cancers that may be treated by the invention include, but are not limited to, non-small cell lung cancer, small-cell lung cancer, colorectal cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer and penile cancer.
Combination Formulations and Uses Thereof The compounds of the invention can be combined with one or more therapeutic agents. In particular, the therapeutic agent can be one that treats or prophylactically treats any cancer described herein.
Combination TherapiesA compound of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of treatment to treat cancer. In combina tion treatments, the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:83-86, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect.In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog. Also included is 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cydosphosphamide; alkyl 166 WO 2022/103899 PCT/US2021/058865 sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietytenephosphoramide, triethiylenethiophosphoramide and trimethylotomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and caiicheamicin omegall (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, Adriamycin® (doxorubicin, including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5- FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testoiactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin;phenamet; pirarubicin; losoxantrone; podophyilinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2‘,2"-trichlorotriethylamine; trichothecenes (especially T- toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine;mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABraxane®, cremophor- free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, III.), and Taxotere® doxetaxeI (Rhone-Poulenc Rarer, Antony, France); chloranbucil;Gemzar®gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; 167 WO 2022/103899 PCT/US2021/058865 difluoromethytornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail to be administered in combination with the first therapeutic agent described herein. Suitable dosing regimens of combination chemotherapies are known in the art and described in, for example, Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.In some embodiments, the second therapeutic agent is a therapeutic agent which is a biologic such a cytokine (e.g., interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (Avastin®). In some embodiments the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response, or antagonizes an antigen important for cancer. Such agents include Rituxan (Rituximab); Zenapax (Daclizumab); Simulect (Basiliximab); Synagis (Palivizumab); Remicade (Infliximab); Herceptin (Trastuzumab); Mylotarg (Gemtuzumab ozogamicin); Campath (Alemtuzumab); Zevalin (Ibritumomab tiuxetan); Humira (Adalimumab); Xolair (Omalizumab); Bexxar (Tositumomab-l-131); Raptiva (Efalizumab); Erbitux (Cetuximab); Avastin (Bevacizumab); Tysabri (Natalizumab); Actemra (Tocilizumab); Vectibix (Panitumumab); Lucentis (Ranibizumab); Soliris (Eculizumab); Cimzia (Certolizumab pegol); Simponi (Golimumab); Haris (Canakinumab); Stelara (Ustekinumab); Arzerra (Ofatumumab); Prolia (Denosumab); Numax (Motavizumab); ABThrax (Raxibacumab); Benlysta (Belimumab); Yervoy (Ipiiimumab); Adcetris (BrentuximabVedotin); Perjeta (Pertuzumab); Kadcyla (Ado-trastuzumab emtansine); and Gazyva (Obinutuzumab). Also included are antibody-drug conjugates.The second agent may be a therapeutic agent which is a non-drug treatment. For example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia and/or surgical excision of tumor tissue.The second agent may be a checkpoint inhibitor. In one embodiment, the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, e.g., humanized or fully human. In some embodiments, the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab,Yervoy or tremelimumab). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/Opdivo®; pembrolizumab/Keytruda®; pidilizumab/CT-01 1). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MED14736 MSB00107180; BMS 936559). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/lg fusion protein such as AMP 224). In some embodiments, the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAGS, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, ora combination thereof. 168 WO 2022/103899 PCT/US2021/058865 ؛n any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially, in either order. The first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to hours, upto 22 hours, upto 23 hours upto 24 hours or up to 1-7, 1-14, 1-21 or 1-30 days before or after the second therapeutic agent.
Pharmaceutical Compositions The compounds of the invention are preferably formulated into pharmaceutical compositions for administration to a mammal, preferably, a human, in a biologically compatible form suitable for administration in vivo. Accordingly, in an aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.The compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention. In accordance with the methods of the invention, the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, ortransdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepitheiiaS, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.A compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard- or soft-shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. A compound of the invention may also be administered parenterally. Solu tions of a compound of the invention can be prepared in water suitably mixed with a surfactant. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington ’s Pharmaceutical Sciences (2003, 20th ed.) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing 169 WO 2022/103899 PCT/US2021/058865 device. Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as compressed air or an organic propellant. The aerosol dosage forms can also take the form of a pump-atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base. A compound described herein may be administered intratumorally, for example, as an intratumoral injection. Intratumoral injection is injection directly into the tumor vasculature and is specifically contemplated for discrete, solid, accessible tumors. Local, regional, or systemic administration also may be appropriate. A compound described herein may advantageously be contacted by administering an injection or multiple injections to the tumor, spaced for example, at approximately, 1 cm intervals. In the case of surgical intervention, the present invention may be used preoperatively, such as to render an inoperable tumor subject to resection. Continuous administration also may be applied where appropriate, for example, by implanting a catheter into a tumor or into tumor vasculature.The compounds of the invention may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
Dosages The dosage of the compounds of the invention, and/or compositions comprising a compound of the invention, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. The compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the invention are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg. Dose ranges include, for example, between 10-1000 mg.Alternatively, the dosage amount can be calculated using the body weight of the patient. For example, the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-100 mg/kg.
Examples Definitions used in the foilowing Schemes and elsewhere herein are: MeCN orACN acetonitrileAIBNBoct-BuOKDAST azobisisobutyronitriie tert-butoxycarbonyl potassium tert-butoxide diethylaminosulfur trifluoride 170 WO 2022/103899 PCT/US2021/058865 DCE dichtoroethaneDCM dichtoromethaneDCPP-2HBF4 1,3-bfs(dicyclohexylphosphino)propane bis(tetrafluoroborate)DEA N.N-diethylamineDMP Dess-Martin periodinane, 1,1,1-Tris( acetyloxy )-1,1-dihydro-1 ,2-DIAD diisopropyl azodicarboxylateDIBAL-H diisobutylaluminum hydrideDIEA or DIPEA N,N-diisopropylethylamineDMA dimethylacetamideDMAP 4-(dimethylamino)pyridineDME 1,2-dimethoxyethaneDMF N,N-dimethylformamideDMSO dimethylsulfoxidedppfEDCIbis(diphenylphosphino)ferrocene-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochlorideESI electrospray ionizationEtsN or TEA triethylamineEA ethyl acetateEtOH ethyl alcoholFA formic acidFCC flash column chromatographygHATUgrams2-(3H-[ 1,2,3 ]triazolo[ 4,5-b ]pyridin-3-yl)4, 1,3 ,3- tetramethylisouroniumHCI hydrochloric acidHOAc acetic acidHOBt hydroxybenzotriazoleHPLC high performance liquid chromatographyIPA isopropyl alcoholL literLCMS liquid chromatography / mass spectrometrym-CPBA 3-chloroperoxybenzoic acidMeCN acetonitrileMel methyl iodideMeOH methyl alcoholmL millilitermmol millimolemgMHzmilligrams megahertzMS mass spectrometryMTBE methyl tert-butyl etherm/z mass/charge ratio 171 WO 2022/103899 PCT/US2021/058865 NBS N-bromosuccin imideNIS N-iodosuccinimidenm nanometerNMR nuclear magnetic resonancePE petroleum etherPhMe tolueneppm parts per millionrt room temperatureRT retention timeSFC supercritical fluid chromatographySPhos Pd G3 (2-dicyclohexylphosphino-2 ’,6’-dimethoxybiphenyl) [2-(2’-amino-,T-biphenyl)]pailadium(ll) methanesulfonateTBS tert-butyldimethylsiiylTBSCI tert-butyldimethylsiiyl chlorideTBDMS tert-butyldimethylsiiyl chlorideTFA trifluoroacetic acidTFAA trifluoroacetic anhydrideTHF tetrahydrofuranTMSCN trimethylsilyl cyanideTosMIC toluenesulfonylmethyl isocyanideZiram zinc dimethyidith iocarbamate MaterialsUnless otherwise noted, ail materials were obtained from commercial suppliers and were used without further purification. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere.Table IC lists compounds of the invention prepared using methods described herein.
TableIC. Compounds of the invention 172 WO 2022/103899 PCT/US2021/058865 173 WO 2022/103899 PCT/US2021/058865 174 WO 2022/103899 PCT/US2021/058865 175 WO 2022/103899 PCT/US2021/058865 176 WO 2022/103899 PCT/US2021/058865 MaterialsUnless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. Ail reactions involving air- or moisture-sensitive reagents were performed under anitrogen atmosphere.
Example 1. Preparation of Intermediates Intermediate 1. 2,3-Dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1 -dioxide K2CO3s DMF, 25 1־־C,16 hrs Siep 3 Oxone --------------------- MeOH/H2O Na2S DMF, 6 hrs Step 1 NaH THE 0°C h4 ؛ a ؛ l THF 0 °C, 1 hss Step 2 Pd(OAc)2, dcpp, K2CO3, CO DMSO/H2O,100 °C,4 hrs Step 4 Step 5 Step S Bntermediat® 1 Step 1: Preparation of methyl 4-bromo-2-mercaptobenzoate To a solution of methyl 4-bromo-2-fluoro-benzoate (100 g, 429.12 mmol) in DMF (1 L) was added sodium sulfide (33.49 g, 429.1 mmol, 18.0 mb) and the mixture was stirred at 30°C for 16 h. The mixture was poured into water (6000 mL) and then was adjusted pH to -3 with 2N HCI. The mixture wasextracted with MTBE (3000 mb x 2). The combined organic phase was washed with brine (3000 mb x 3), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give methyl 4-bromo-2- mercaptobenzoate (103 g, crude) as yellow oil, which was used for the next step without further purification. 177 WO 2022/103899 PCT/US2021/058865 1H NMR (400 MHz, DMSO״d6) 6 = 7.91 (d, J= 1.6 Hz, 1H), 7.83 - 7.81 (m, 1H), 7.43-7.40 (m, 1H), 5.(brs, 1H), 3.83 (s, 3H) ppm Step 2: Preparation of (4-bromo-2-mercaptophenyi)methanol To a mixture of methyl 4-bromo-2-mercaptobenzoate (103 g, 416.82 mmol) in THF (1000 mb) was added LiAIH4 (15.82 g, 416.82 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 hr. The mixture was poured into 1N HCI (2000 mb) and extracted with EtOAc (2000 mb x 2). The combined organic phase was washed with brine (2000 mb), dried over anhydrous N82SO4, filtered and concentrated under vacuum to give (4-bromo-2-mercaptophenyl)methanol (88 g, crude) as yellow oil, which was used for the next step without further purification.1H NMR (400 MHz, DMSO_d6) 6 = 7.59 (s, 1H), 7.32 (d, J= 1.2 Hz, 2H), 5.56 - 5.36 (m, 2H), 4.39 (s, 2H) ppm Step 3: Preparation of (4-bromo-2~(vinylthio)phenyi)methanol and (4-bromo-2-((2- bromoethyi)thio)phenyl)methanol To a mixture of (4-bromo-2-mercaptophenyl)methanol (85 g, 387.95 mmol) in DMF (1700 mb) was added K2CO3 (160.9 g, 1.16 mol) and 1,2-dibromoethane (218.6 g, 1.16 mol, 87.8 mb) and the mixture was stirred at 25 °C for 1 hr. Then the mixture was stirred at 70 °C for another 24 h. The reaction mixture was poured into Sat.NH4CI (10 L) and extracted with EA (3000 mL*2). The combined organics were washed with brine (4000 mb x 2), dried over Na2SO4, filtered and filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography (PE/EA=50/1 to 5/1). The fraction was concentrated in vacuum to give f4-bromo-2-(vinylthio)phenyl)methanol (33.5 g, 136.66 mmol, 35% yield) and (4-bromo-2-((2-bromoethyl)thio)phenyl)methanol (10 g, 30.67 mmol, 8% yield) as yellow oil. (4-bromo-2-(vinylthio)phenyl) methanol:1H NMR (400 MHz, CDCb) 6 = 7.55 (s, 1H), 7.45 (d, J=2 Hz, 1H), 7.43 (d, J=2 Hz, 1H), 6.49-6.42 (m, 1H), 5.45 (d, J=9.6 Hz, 1H), 5.32 (d, J=10.4 Hz, 1H), 4.73 (s, 2H) ppm. (4-bromo-2-((2-bromoethyl)thio)phenyl)methanol:1H NMR (400 MHz, CDCb) 6 = 7.46 (s, 1H), 7.33 (d, J=2 Hz, 1H), 7.09 (d, J=2 Hz, 1H), 6.67 (s, 2H), 3.41- 3.38 (m, 2H), 3.25-3.23 (m, 1H) ppm.
Step 4: Preparation of (4-bromo-2-(vinylsulfonyl)phenyl)methanol To a mixture of (4-bromo-2-(v!nylthio)phenyl)methanol (35.5 g, 144.82 mmol) in MeOH (350 mb) and H2O (350 mb) was added Oxone® (133.54 g, 217.23 mmol) and the mixture was stirred at 25 °C for h. Water (1500mL) was added and the mixture was extracted with EtOAc (1500 mb x 2). The combined organic phase was washed with brine (1000 mb x 2), dried over anhydrous N82SO4, filtered and concentrated under vacuum to give (4-bromo-2-vinylsulfonyl-phenyl)methanol (38.5 g, crude) as a yellow solid, which was used for the next step without further purification. ,H NMR (400 MHz, DMSO_d6) 5 = 7.98- 7.95 (m, 2H), 7.77- 7.75 (m, 1H), 7.22-7.15 (m, 1H), 6.43- 6.39 (m, 1H), 6.31 (d, J = 10.0 Hz, 1H), 5.62-5.59 (m, 1H), 4.75 (d, J = 5.2 Hz, 2H) ppm 178 WO 2022/103899 PCT/US2021/058865 Step 5: Preparation of 8-bromo-2,3-dihydro-5H-benzo[e][1,4]oxathiepine 1,1-dioxide To a mixture of (4-bromo-2-vinylsulfonyl-phenyl)methanol (38.5 g, 138.9 mmol) in DMF (10mL) was added NaH (11.11 g, 277.84 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at °C for 1 hr. The reaction mixture was poured into sat. NH4CI (2 L) and extracted with EA (2000 mL*2). The combined organic phase was washed with brine (2000 mL), dried over anhydrous N32SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:EtOAc=50:1-5:1) and concentrated in vacuum to give 8-bromo-2,3-dihydro-5H- benzo[ej[1,4]oxathiepine 1,1-dioxide (26.5 g, 95.62 mmol, 69% yield) as a white solid.1H NMR (400 MHz, DMSO_d6) 6 = 7.99 (d, J = 2.0 Hz, 1H), 7.92-7.90 (m, 1H), 7.55 (d, J= 8.0 Hz, 1H), 4.88 (s, 2H), 4.20 - 4.17 (m, 2H), 3.68 - 3.66 (m, 2H) ppm Step 6: Preparation of 2,3-dihydro-5H-benzo[e][1,4]oxath!epine-8-carboxylic acid 1,1-dioxide (intermediate 1) To a mixture of 8-bromo-2,3-dihydro-5H-benzo[e][1,4]oxathiepine 1,1-dioxide (8.8 g, 31.75 mmol) in DMSO (90 mL) and H2O (9 mL) was added 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (3.89 g, 6.35 mmol), K2CO3 (6.58 g, 47.63 mmol) and Pd(OAc)2 (712.90 mg, 3.mmol). The mixture was purged with CO for three times and then was stirred at 100 °C under CO (psi) for 4 h. Water (3000 mL) was added and the mixture was extracted with EtOAc (500 mL x 2) and then the organic phase was discarded. The aqueous layer was adjusted pH to ~3 with 1N HCI. Then the mixture was extracted with EA (500 mL*5). The combined organic phase was washed with brine (20mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude was washed by MTBE (20 mL*2), then filtered, the filter cake was evaporated to dryness to give 2,3-dihydro-5H- benzo[e][1,4]oxathiepine-8-carboxyiic acid 1,1-dioxide (15 g, 61.92 mmol, 65% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) b = 8.43 (s, 1H), 8.20-8.18 (m, 1H), 7.72-7.70 (m, 1H), 4.96 (s, 2H), 4.23- 4.20 (m, 2H), 3.67-3.66 (m, 2H) ppm.
Intermediate 2. 3,5-Dihydro-2H-[1,4]oxathiepino[6,5-b]pyr!dine-8-carboxylic acid 1,1-dioxide Br Na2S DMF, RT, 2 hrs Step 2 K2CO31 DMF, 60 °C,12 hrs Sr Step 1 Oxone MeOH/H2O 0 °C to RT Step 4 NaH DMF, 0eC DMSO/H2O, 100 nC, 12 hrs Pti(OAc)2, depp, KCO3 CO Step 3 Oxone MeOH/H2O 0 "C to RT intermediate 2 Step 5 Stags 8 Step 7 Step 1: Preparation of methyl 5-bromo-3-mercaptopicolinate To a solution of methyl 5-bromo-3-fluoro-pyridine-2-carboxylate (1 g, 4.27 mmol) in DMF (10 mL) was added Na2S (333.49 mg, 4.27 mmol). The mixture was stirred at 25 °C for 2 h. Three of the same batches were combined and purified together. The mixture was diluted with water (50 mL) and adjusted to pH=5 with 1N aq. HCI. The mixture was extracted with EA (50 mL x 2). The combined organic layer was washed by brine (50 mL x 2), dried with anhydrous Na2SO4 and concentrated to afford methyl 5- bromo-3-mercaptopicolinate (3.3 g, crude) as a brown oil. LCMS (ESI) m/z: [M-؛-Hj+ = 247.8/249.8 179 WO 2022/103899 PCT/US2021/058865 Step 2: Preparation of (5-bromo-3-mercaptopyndin-2-yf)methanol To a solution of methyl 5-bromo-3-mercaptopicolinate (3.3 g, 13.30 mmol) in THE (33 mL) was added LiAIH4 (504.8 mg, 13.30 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (100 mL) and adjusted to pH=6 with 1N aq. HCI. Then the mixture was extracted with EA (100mL x2). The combined organic layer was dried over anhydrous N82SO4 and concentrated to afford (5-bromo-3-mercaptopyrid!n-2-yl)methanol (1.66 g, 7.54 mmol) as a brown oil. LCMS (ESI) m/z: [M+HF = 219.8/221.8.
Step 3: Preparation of (5-bromo-3~(vinylthio)pyridin~2-yl)methanoi To a solution of (5-bromo-3-mercaptopyridin-2-yl)methanol (1.66 g, 7.54 mmol) in DMF (15 mL) was added K:CO: (3.13 g, 22.63 mmol) and 1,2-dibromoethane (7.08 g, 37.71 mmol, 2.85 mL). The mixture was stirred at 60 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 2). The combined organic layer was dried with anhydrous N32SO4 and concentrated to afford residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash ® Silica Flash Column, Eluent of 0-100% Ethylacetate/Petroleum ether). The eluent was concentrated to afford (5-bromo-3-(vinylthio)pyridin-2-yl)methanol (600 mg, 2.44 mmol, 32% yield) as a brown oil. LCMS (ESI) m/z: [M+HF = 245.9/247.9.1HNMR (400 MHz, DMSO-da) 5 = 8.53 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 6.81 - 6.74 (m, 1H), 5.64 - 5.51 (m, 2H), 5.32 - 5.29 (m, 1H), 4.54 (d, J = 6.0 Hz, 2H) ppm.
Step 4: Preparation of (5-bromo-3-(vinyteulfmyl)pyridirs-2-yl)metbarsoi To a solution of (5-bromo-3-(vinylthio)pyridin-2-yl)methanol (600 mg, 2.44 mmol) in MeOH (6 mL) was added Oxone® (824.27 mg, 1.34 mmol) in water (6 mL) slowly at 0 °C. The mixture was stirred at °C for 1 hr. The mixture was quenched by saturated aq.Na2SO3 (30 mL) and extracted with EA (30 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to afford residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethylacetate/Petroleum ether). The eluent was concentrated to afford (5- bromo-3-(vinylsulfinyl)pyridin-2-yl)methanol (500 mg, 1.91 mmol, 78.25% yield) as a colorless oil. 1HNMR (400 MHz, DMSO-d6) 6 = 8.74 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.18 - 7.12 (m, 1H), 6.09 - 6.02 (m, 2H), 5.95 (d, J = 9.6 Hz, 1H), 4.85 - 4.78 (m, 1H), 4.73 - 4.66 (m, 1H) ppm.
Step 5: Preparation of 8-bromo-3,5-dihydro-2H-[1,4]oxathiepmo[6,5-b]pyridine 1-oxide To a solution of (5-bromo-3-(vinylsulfinyl)pyridin-2-yl)methanol (500 mg, 1.91 mmol) in DMF (mL) was added NaH (152.59 mg, 3.81 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was quenched by saturated aq. NH4CI (30 mL) and extracted with EA (30 mL x2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to afford residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethylacetate/Petroleum ether). The eluent was concentrated to afford 8-bromo-3,5- dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine 1-oxide (350 mg, 1.34 mmol, 70% yield) as a colorless oil. 1HNMR (400 MHz, DMSO-d8) 6 = 8.75 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 4.91 - 4.74 (m, 2H), 43-4 34 (m, 1H), 4.21 -4.18(m, 1H), 3.65 - 3.56 (m, 1H), 3.49 - 3.44 (m, 1H) ppm. 180 WO 2022/103899 PCT/US2021/058865 Step 6: Preparation of 3,5-dihydro-2ff-[1,4]oxathiepmo[6,5-b]pyridirie-8-carboxyiic acid 1-oxide To a solution of 8-bromo-3,5-dihydro-2H-[1,4joxathiepino[6,5-b]pyridine 1 -oxide (350 mg, 1.mmol) in DMSO (4 mb) and water (120.27 mg, 6.68 mmol, 120.27 ub) was added 1,3- bis(d!cyclohexylphosphino)propane bis(tetrafluoroborate) (81.75 mg, 133.52 pmol), K2CO3 (276.82 mg, 2.00 mmol) and Pd(OAc)2 (29.98 mg, 133.52 pmol). The mixture was degassed and purged with CO for times. The mixture was stirred at 100 °C for 12 h under CO (15 psi) atmosphere. The mixture was filtered and washed by DMSO (2 mb) and water (2 mb). Then the filter liquid was adjusted to pH=6 with 1N aq. MCI. The filter liquid was purified by reversed-phase HPLC (0.1% FA condition). The eluent was concentrated to remove ACN and lyophilized to afford 3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8- carboxylic acid 1-oxide (70 mg, 0.262 mmol, 20% yield) as a white solid.LCMS (ESI) m/z: [M+Hp = 227.9.1HNMR (400 MHz, DMSO-ds) 5 = 9.03 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 5.01 - 4.88 (m, 2H), 4.43.4.41 (m, 1H), 4.18 - 4.15 (m, 1H), 3.63 - 3.62 (m, 2H), 3.52 - 3.48 (m, 2H) ppm.
Step 7: Preparation of 3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxyiic acid 1,1-dioxide (Intermediate 2) To a solution of 3,5-dihydro-2H-[1,4]oxathiepino[6,5-b]pyridine-8-carboxylicacid 1-oxide (70 mg, 0.309 mmol) in MeOH (0.7 mb) was added Oxone® (284.07 mg, 462.07 pmol) in water (0.7 mb) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The mixture was filtered. The filter cake was washed by MeOH (5 mb). Then the filter liquid was quenched by saturated Na2SO3 solution. Then the solution was purified by reversed-phase HPLC (0.1% FA condition). The eluent was concentrated to remove ACN and lyophilized to afford 3,5-dihydro-2H-[1,4]oxathlepino[6,5-b]pyridine-8-carboxylic acid 1,1-dioxide (36 mg, 136.16 pmol, 44% yield) as a white solid.LCMS (ESI) m/z: [M+Hf = 243.9.
Intermediate 3. 3,4-Dihydro-2H-benzo[b][1,4]oxatbiepme-7-carboxylic add 5,5-dioxide hso3c! 20 °C. 18 hrs Stag 1 PPh3 toluene, 80 °C, 2 hrs Step 2 Conc>E2SO4 MeOH, 70 aC, 40 hrs Step 3 Cs2CO3l DMF, 20 °C، 2 hrs MeOH, H2O, 20 °C, 16 hrs Oxone NaOH MeOH, H2O, 20 eC. 2 hrs Step 4 Step 5 Step 6 antermedsat® 3 Step 1: Preparation of 3-chlorosulfonyl-4-hydroxy-benzoic acid To a solution of HSO:C! (31 mL) was added portionwise 4-hydroxybenzoic acid (5.5 g, 39.mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was dropwise added slowly ice water (300 mb). The mixture was extracted with ethyl acetate (100 mb x 3). The combined organic layers were washed with brine (50 mb), dried over Na2SO4, concentrated in vacuo to give a residue. The 181 WO 2022/103899 PCT/US2021/058865 crude product was triturated with PE (30 ml) at 20 °C for 30 min to afford 3-chlorosulfonyl-4-hydroxy- benzoic acid (4.5 g, 13.72 mmol, 74% yield) as a white solid.1HNMR (400 MHz, DMSO-d5) 0 = 8.09 - 8.06 (m, 1H), 7.82 - 7.75 (m, 1H), 6.89 - 6.81 (m, 1H) ppm.
Step 2: Preparation of 4-hydroxy-3-mercaptobenzoic acid To a solution of 3-chlorosulfonyl-4-hydroxy-benzoic acid (1 g, 4.23 mmol) in toluene (20 mL) was added PPh3 (3.88 g, 14.79 mmol) in portions. The mixture was stirred at 90 °C for 2 h. The reaction was quenched by adding 10% NaOH solution (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The aqueous phase was adjusted to pH 2 with 1N HCI. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 4- hydroxy-3-mercaptobenzoic acid (0.62 g, 3.64 mmol, 86.21% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) 5 =12.34 (s, 1H), 7.89 - 7.83 (m, 1H), 7.61 - 7.52 (m, 1H), 6.90 - 6.83 (m, 1H), 5.01 (s, 1H) ppm.
Step 3: Preparation of methyl 4-hydraxy-3-mercaptobenzoate To a solution of 4-hydroxy-3-mercaptobenzoic acid (0.6 g, 3.53 mmol) in MeOH (5 mL) was added dropwise H2SO4 (352.84 mg, 3.53 mmol, 191.76 uL, 98% purity). The mixture was stirred at 70 °C for 40 h. The reaction was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo to give methyl 4-hydroxy-3-mercaptobenzoate (0.6 g, crude) as white solid. 1H NMR (400 MHz, DMSO-d6) 6 = 11.30 (s, 1H), 8.07 - 8.01 (m, 1H), 7.77-7.71 (m, 1H), 6.99 - 6.95 (m, 1H), 3.80-3.78 (m, 3H) ppm.
Step 4: Preparation of methyl 3,4-dlhydro-2H-berszo[b][1,4]oxatbtepine-7-carboxylate To a solution of methyl 4-hydroxy-3-mercaptobenzoate (0.1 g, 542.85 pmol, 1 eq) in DMF (5 mL) was added CS2CO3 (884.36mg, 2.71 mmol) and dropwise 1,3-dibromopropane (109.6 mg, 0.543 mmol, uL). The mixture was stirred at 20 °C for 2 h. The reaction was quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over NazSO4, concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1), the eluent was concentrated in vacuo to afford methyl 3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxylate (65 mg, 0.274 mmol, 51% yield) as yellow oil.LCMS (ESI) m/z: [M+Hp = 225.1.1H NMR (400 MHz, CDCb) 6 = 8.09 - 8.02 (m, 1H), 7.83 - 7.74 (m, 1H), 7.03 - 6.94 (m, 1H), 4.45 - 4.(m, 2H), 3.93 - 3.84 (m, 3H), 3.10 - 2.98 (m, 2H), 2.34 - 2.22 (m, 2H) ppm.
Step 5: Preparation of methyl 3,4-dlhydro-2H-benzo[b][1,4]oxathiepine-7-carboxylate 5,5-dioxide A mixture of methyl 3,4-dihydro-2H-1,5-benzoxathiepine-7-carboxylate (60 mg, 267.53 pmol) in MeOH (5 mL) and H; 182 WO 2022/103899 PCT/US2021/058865 in vacuo to give methyl 3,4-dihydro-2H-benzo[b][1,4]oxath!epine-7-carboxylate 5,5-dioxide (66 mg, 0,2mmol, 96% yield) as yellow oil,1H NMR (400 MHz, CDCI3) 6 = 8.73 - 8.60 (m, 1H), 8.32 - 8.16 (m, 1H), 7.26 - 7.23 (m, 1H), 4.43 - 4.(m, 2H), 3.97 - 3.91 (m, 3H), 3.48 - 3.36 (m, 2H), 2.53 - 2.41 (m, 2H) ppm.
Step 6: Preparation of3,4-dihydro-2H-benzo[b][t,4joxathiepine-7-carboxylic acid 5,5-dioxide (intermediate 3) A mixture of methyl 3,4-dihydro-2H-benzo[b][1,4]oxathiepine-7-carboxylate 5,5-dioxide (65 mg, 0.254 mmol) in MeOH (3mL) and H: Intermediate 4. 6-Chioro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide h2so4MeOH, 70 °C. 8 hrsStep 1 N32SDMF, 25 °C. 2 hrsStep 2 LIAiH4THF, 0 °C. 1 hrStep 3 K2CO3, DMF.°C, 16 hrsPd(OAc} 2, Xphos, TEA, CO (15 psi)--------------------------MeOH, 70 °C .8 hrsStep S MeOH, H2O, °C, 2 hrs-----------------OxoneStep 6 Step 4 Step 1: Preparation of methyl 4-bromo-2-chloro-6-fluorobenzoate To a solution of 4-bromo-2-chioro-6-fiuorobenzoic acid (10 g, 39.46 mmol) in MeOH (90 mL) was added cone. H2SO4 (18.4g, 187.60 mmol, 10 mL) slowly, then the mixture was stirred at 70 °C for 8 h. The mixture was concentrated under vacuum to remove part of MeOH, then poured into sat. NaHCO(200 mL), then extracted with EA (200 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over N82SO4, filtered and concentrated under reduced pressure to give methyl 4- bromo-2-chloro-6-fluorobenzoate (9.2 g, crude) as colorless oil, and used to next step directly. 1H NMR (400 MHz, DMSO-ds) 5 = 7.87 - 7.76 (m, 2H), 3.91 (s, 3H) ppm. 183 WO 2022/103899 PCT/US2021/058865 Step 2: Preparation of methyl 4-bromo-2-chioro-6-mereaptobenzoate To a solution of methyl methyl 4-bromo-2-chloro-6-fluorobenzoate (7.2 g, 26.92 mmol) in DMF (72 mL) was added Na2S (2.10 g, 26.92 mmol), then the mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (300 mL), then the resulting mixture was acidized to pH 3 with 1N HCI solution, extracted with EA (200 mL x 2). The combined organic layers were washed with brine (250 mL x 2), dried over N32SO4, filtered and concentrated under reduced pressure to give methyl 4-bromo-2-chloro-6- mercaptobenzoate (7 g, crude) as yellow oil, the crude product was used to next step directly.
Step 3: Preparation of (4-bromo-2~chtoro-6-mercaptophenyl)methanol To a mixture of methyl methyl 4-bromo-2-chloro-6-mercaptobenzoate (9 g, 31.97 mmol) in THF (90 mL) was added LIAIH4 (1.33 g, 35.16 mmol) at 0 °C, then the mixture was stirred at 0 °C for 1 hr. The mixture was poured into HCI (1 N, 200 mL), then extracted with EA (250 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give (4-bromo-2-chloro-6-mercaptophenyl)methanol (5.8 g, crude) as a colorless oil Step 4: Preparation of (4-bromo-2-chtoro-6-(vinyhhio)phenyl)methanol To a mixture of (4-bromo-2-chloro-6-mercaptophenyl)methanol (5.7 g, 22.48 mmol ) in DMF (1mL) was added K2CO3 (9.32 g, 67.44 mmol) and 1,2-dibromoethane (21.12 g, 112.41 mmol, 8.5 mL), then the mixture was stirred at 25 °C for 12 h. The mixture was poured into water (200 mL) and extracted with EA (100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE/EA = 10/1 to 1:1, SiO2) and the elution was evaporated to give (4-bromo-2-chloro-6-(vinylthio)phenyl)methanol (2.7 g, 9.mmol, 43% yield) as colorless oil.1H NMR (400 MHz, DMSO-d6) 7.65 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 6.78 - 6.71 (m, 1H), 5.61 -5.52 (m, 2H), 5.25-5.23 (m, 1H), 4.62 (d, 5.2 Hz, 2H) ppm Step 5: Preparation of methyl 3-chioro-4-(hydroxymethyl)-5-(vinySthio)benzoate To a mixture (4-bromo-2-chloro-6-(vinylthio)phenyl)methanol (1000 mg, 3.58 mmol) in MeOH (mL) and TEA (10 mL) was added Pd(OAc)2 (80.30 mg, 357.68 pmol) and XPhos (341 mg, 0.715 mmol), then the mixture was degassed and purged with CO (15 psi) for 3 times, and then the mixture was stirred at 70 °C for 8 h under CO (15psi) atmosphere. The mixture was diluted with water (20 mL), was extracted with EA (15 mL x 3), the combined organic phase was washed with brine (30 mL), dried over N32SO4, filtered and concentrated under vacuum to give a crude product. The residue was purified by column chromatography (SIO2, Petroleum ether/Ethyl acetate=20/1 ؛ to 5/1). The fraction was concentrated under vacuum to give methyl 3-chloro-4-(hydroxymethyl)-5-(vinylthio)benzoate (650 mg, 2.36 mmol, 66% yield) as a white solid.,H NMR (400 MHz, DMSO-ds) 6= 7.83 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 1.6 Hz. 1H), 6.74-6.67 (m, 1H), 5.62- 5.51 (m, 2H), 5.36-5.33 (m, 1H), 4.70 (d, J = 5.2 Hz, 2H), 3.87 (s, 3H) ppm Step 6: Preparation of methyl 3-chtoro-4-(hydroxymethyi)-5-(v!nyisulfonyl)benzoate 184 WO 2022/103899 PCT/US2021/058865 To a mixture of methyl 3-chloro-4-(hydroxymethyl)-5-(vinylthio)benzoate (500 mg, 1.93 mmol) in H2O (5 ml) and MeOH (5 mL) was added Oxone® (3.56 g, 5.80 mmol), the mixture was stirred at 25 °C for 1 hr. The mixture was diluted with water (200 mL), then extracted with EA (250 mL x 2), the combined organic solution was washed with sat.Na2SO3 (150 mL x 2) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 3-chloro-4-(hydroxymethyl)-5- vinylsulfonyl-benzoate (560 mg, crude) was obtained as a yellow oil LCMS (ESI) m/z: [M+H]* = 273.1H NMR (400 MHz, DMSO-d6) 6= 8.42 (d, J= 1.6 Hz, 1H), 8.27 (d, J= 1.6 Hz, 1H), 7.34 - 7.27(m, 1H), 6.47 - 6.31 (m, 2H), 5.52 - 5.49 (m, 2H), 4.98 (d, J = 5.2 Hz, 2H), 3.91 (s, 3H) ppm.
Step 7: Preparation of 6-cbloro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1- dioxide (intermediate 4) To a mixture of methyl 3-chloro-4-(hydroxymethyl)-5-vinylsulfonyl-benzoate (560 mg, 1.93 mmol) in THF (18 mL) was added NaH (154.09 mg, 3.85 mmol, 60% purity) at 0 °C , the mixture was stirred at °C for 1 hr. The mixture was diluted with water (10 mL) and MeOH (5 mL), then stirred at 25 °C for min, the resulting mixture was diluted with water (100 mL), acidized to pH 2 with HCI (1 N), the resulting solution was extracted with EA (150 mL x2), The combined organic layers were washed with brine (2mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-chloro-2,3-dihydro- 5H-benzo[e]n ,4]oxathiepine-8-carboxylic acid 1,1-dioxide (300 mg, crude) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 6=13.91 -13.84 (m, 1H), 8.38 (d, J= 1.6 Hz, 1H), 8.22 (d, J= 1.6 Hz, 1H), 5.19 (s, 2H), 4.23-4.21 (m, 2H), 3.79-3.77 - 3.74 (m, 2H) ppm.
Intermediate 5: 6-Huoro-2,3-dihydro-5£f-benzo[e][1,4]oxathiepme-8-carboxylic acid 1,1-dioxide PMBSH, Cs 2CO3DMF, 60 °C, 2 hrsStep 1 mCPBA DCM, RTK2CO3, DMF, °C, 16 hrs Step 4 DMSO, H2O, 100 "C, 4 hrs Br Pd(OAc) 5, depp K2CO3, CO (15 psi) Step 7 Steps Step 1: Preparation of methyl 4-bromo-2-fiuoro-6-((4-methoxybenzyS)thio)benzoate To a mixture of methyl 4-bromo-2,6-difluoro-benzoate (5 g, 19.92 mmol) and (4- methoxyphenyl)methanethiol (3.07 g,19.92 mmol, 2.77 mL) in DMF (50 mL) was added C52CO3 (12.98 g, 39.84 mmol), then the mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (400 mL), 185 WO 2022/103899 PCT/US2021/058865 the extracted with EA(2Q0 mL x 3), the combined organic layers was washed with brine(200 mL x 2), then dried over N32SO4, filtered and concentrated under vacuum to give methyl 4-bromo-2-fluoro-6-((4- methoxybenzyl)thio)benzoate (9 g, crude) as yellow oil, which was used to next step directly.1H NMR (400 MHz, DMSO-de) 6=7.54■ - 7.51 (m, 2H), 7.29 - 7.26 (m, 2H), 6.90 - 6.87 (m, 2H), 4.29 (s, 2H), 3.83 (s, 3H), 3.73 - 3.72 (m, 3H) ppm.
Step 2: Preparation of methyl 4-bromo~2-fluoro-6-mercaptobenzoate A mixture ofmethy4-bromo-2-fluoro-6-{4-methoxybenzyl)thio)benzoate (9 g, 23.36 mmol) in TFA (138.60g, 1.22 mol, 90 mL) was stirred at 60 °C for 2 h. The mixture was evaporated and then neutralized with by sat.NaHCO: to pH 7. Then the mixture was extracted with EA (200 mL). The organic layer was separated and dried over anhydrous N32SO4. The organic phase was concentrated under vacuum to give methyl 4-bromo-2-tluoro-6-mercaptobenzoate (6 g, crude) as yellow oil, which was used to next step directly.1H NMR (400 MHz, DMSO-de) 5=7.77 - 7.61 (m, 2H), 3.93 (s, 3H) ppm.
Step 3: Preparation of (4-bromo-2~f!uoro-6-mercaptophenyl)methanol To a mixture of methyl 4-bromo-2-f!uoro-6-mercaptobenzoate (3.4 g, 12.83 mmol) in THF (34 mL) was added LiAIH4 (535.5 mg, 14.11 mmol), then the mixture was stirred at 0 °C for 1 hr. The mixture was quenched with 1N HCI (100 mL) and extracted with EA (50 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give (4-bromo-2-fluoro-6- mercaptophenyl)methanol (3 g, crude) as a yellow oil, which was used to next step directly. 1H NMR (400 MHz, DMSO-d6) 6=7.51 (s, 1H), 7.32 - 7.24 (m, 1H), 4.45 (d, J = 1.2 Hz, 2H) Step 4: Preparation of (4-bromo-Muoro-6-(vmylthio)pheriyl)methanoi To a mixture of (4-bromo-2-fluoro-6-mercaptophenyl)methanol (3 g, 12.65 mmol), K2CO3 (5.25 g, 37.96 mmol) in DMF (60 mL) was added 1,2-dibromoethane (11.89 g, 63.27 mmol), then the mixture was stirred at 25 °C for 15 h. The mixture was poured into water (200 mL) and extracted with EA (100 mL). The combined organic layer was dried over N32SO4, filtered, and concentrated under vacuum to give a residue. The residue was purified by column chromatography (PE/EA = 10/1, SIO2) and the eluent was evaporated to give the (4-bromo-2-fluoro-6-(vinylthio)phenyl)methanol (1.6 g, 6.08 mmol, 48% yield) as colorless oil.1H NMR (400 MHz, DMSO-de) 6=7.47-7.44 (m, 1H), 7.30-7.29 (m, 1H), 6.77-6.70 (m, 1H), 5.59 - 5.52 (m, 2H), 5.22-5.20 (m, 1H), 4.51-4.46 (m, 2H) ppm Step 5: Preparation of (4-bromo-2-tiuoro~6-(viny!sLdfmyl)phenyi)methanoi To a mixture of(4-bromo-2-fluoro-6-(vinylthio)phenyl)methanol (800 mg, 3.04 mmol) in DCM (mL) was added m-CPBA (678.98 mg, 3.34 mmol, 85% purity) at 0 °C, then the mixture was stirred at °C for 1 hr. The reaction mixture was quenched by addition saturated aqueous N32SO3 (20 mL) at 0 °C, and then diluted with H2O (20 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl 186 WO 2022/103899 PCT/US2021/058865 acetate=20/1 to 1/1), The fraction was concentrated under vacuum to give (4-bromo-2-fluoro-6- (v!nylsulfinyl)phenyl)methanol (690 mg, 2.47 mmol, 81% yield) as a yellow solid, LCMS (ESI) m/z: pBrM+Hr = 278.91H NMR (400 MHz, DMSO-de) 6 = 7.74 - 7.71 (m, 1H), 7.61 - 7.60 (m, 1H), 7.12 - 7.06 (m, 1H), 6.05 - 5.92 (m, 2H), 5.85 - 5.82 (m, 1H), 4.75 - 4.71 (m, 1H), 4.63 - 4.58 (m, 1H) ppm Step 6: Preparation of8-bromo-6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine 1-oxide To a mixture of (4-bromo-2-fluoro-6-(vinylsulfinyl)phenyl)methanol (650 mg, 2.33 mmol) in DMF (40 mb) was added NaH (186.3 mg, 4.66 mmol, 60% purity) at 0 °C, then the mixture was stirred at 0 °C for 1 hr. The reaction solution was quenched with saturated aqueous NH4CI 50 mb and extracted with EA (50 mb x 3). The combined organic layers were washed with brine (60 mb x 3), dried over Na: Step 7: Preparation of 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1-oxide To a mixture of 8-bromo-6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine 1-oxide (320 mg, 1.mmol), Pd(OAc)2 (12.87mg, 57.32 pmol) and dicyciohexyl(3- d!cyclohexylphosphan!umylpropyl)phosphonium;ditetrafluoroborate (70.19 mg, 114.64 pmol) in DMSO (mb) and H2O (0.2 mb) was added K2CO3 (475.33 mg, 3.44 mmol), then the mixture was stirred at 100 °C for 4 h under CO (15 psi). The mixture was diluted with water (50 mb) and extracted with EA (30 mb x 3). The aqueous layer was acidized to pH^S by HCI solution (2 M) and extracted with EA (100 mb x 2). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxath ؛ep ؛ne-8-carboxylic acid 1-oxide (210 mg, crude) as a white solid, which was used to next step directly.LCMS (ESI) m/z: [M+H]+ = 244.9 Step 8: Preparation of 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxyl!c acid 1,1- dioxide (Intermediate 5) To a mixture of 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1-oxide (210.00 mg, 859.81 pmol) in MeOH (4 mb) and H2O (4 mb) was added Oxone® (634.30 mg, 1.03 mmol), then the mixture was stirred at 25 °C for 2 h. The mixture was diluted with water (50 mb), then extracted with EA (30 mbx3), the combined organic layers was washed with brine (40 mb x 2), dried over Na2SO4, filtered and concentrated under vacuum to give 6-fluoro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8- carboxylic acid 1,1-dioxide (220 mg, crude) as a white solid, which was used to next step directly. 187 WO 2022/103899 PCT/US2021/058865 Intermediates 6 and 7. (R)-2-Methyi-2,3-dihydro-5H-benzo[e][,4joxathiepine-8-carboxylic acid 1,1- dioxide and (S)-2-methyi-2,3-dihydro-5^-benzo[e][1,4]oxathiepine-8-carboxyiic acid 1,1-dioxide Step 1: Preparation of8-bromo-2-methyl-3,5-dihydro-2H-benzo[eJ[1,4joxathiepine 1,1-dioxide To a solution of 8-bromo-2,3-dihydro-5H-benzo[e][1,4joxathiepine 1,1-dioxide (380 mg, 1.mmol, 641.03 uL) in DMF (5 mb) was added NaH (65.82 mg, 1.65 mmol, 60% purity) at 0°C. The mixture was stirred at 0 °C for 0.5 h. Then Mel (233.55 mg, 1.65 mmol, 102.43 uL) was added slowly at 0 °C. The mixture was stirred at 25 °C for 1.5 h. The mixture was diluted with saturated NH4CI solution (30 mb) and extracted with EtOAc (30 mb x 2). The combined organic layer was dried with anhydrous N32SOand concentrated to afford residue. The residue was purified by reversed-phase HPLC (0.1% FA condition). The eluent was concentrated to remove MeCN and lyophilized to afford 8-bromo-2-methyl- 3,5-dihydro-2H-benzo[e][1,4]oxathiepine 1,1-dioxide (100 mg, 309.11 pmol, 23% yield) as a white solid. LCMS (ESI) m/z: [M+HF = 291.0/292.91HNMR(400 MHz, DMSO-ds) 5 = 7.99 (d,J=2.0 Hz, 1H), 7.95-7.92 (m, 1H), 7.56 (d, J =8.0 Hz, 1H), 4.87 (s, 2H), 4.274.23־ (m, 1H), 4.00- 3.95 (m, 1H), 3.71 -3.62 (m, 1H), 1.14 (d, J = 7.2 Hz, 3H) ppm.
Step 2: Preparation of 2-methyi-3,5-d!hydro-2H-benzQ[e][1,4]oxathsepme-8-carboxyi!c acid 1,1- dioxide To a solution of 8-bromo-2-methyl-3,5-dihydro-2H-benzo[ej[1,4]oxathiepine 1,1-dioxide (100 mg, 343.45 pmol) in DMSO (1 mb) and H2O (30.95 mg, 1.72 mmol, 31 pl) was added 1,3- b!s(dicydohexylphosphino)propane bis(tetrafluoroborate) (21.03 mg, 34.35 pmol), K2CO3 (71.20 mg, 515.18 pmol) and Pd(OAc)2 (7.71 mg, 34.35 pmol). The flask was degassed and purged with CO for times. The mixture was stirred at 100 °C for 4 h under CO (15 psi) atmosphere. The mixture was filtered and washed by EA (2 mLand water (2 mb). Then the mixture was diluted with water (5 mb) and extracted with EA (5 mb x2). The combined organic layer was discarded. The aqueous phase was adjusted pH=with 1N aq. HCI. Then the aqueous phase was extracted with EA (5 mb x2). The combined organic layer was washed by brine (5 mbx2), dried with anhydrous N82SO4 and concentrated to afford 2-methyl- 3,5-dihydro-2H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (80 mg, 0.290 mol, 85% yield) as a white solid.LCMS (ESI) m/z: [M+HF = 256.9. 1HNMR(400 MHz, DMSO-ds) 5 = 8.44 (d, J= 1.6 Hz, 1H), 8.22-8.19 (m, 1H), 7.72 (d, 8.0 Hz, 1H),4.95 (s, 2H), 4.29 -4.25 (m, 1H), 4.03- 3.98 (m, 1H), 3.72-3.60 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H) ppm. 188 WO 2022/103899 PCT/US2021/058865 Step 3: Preparation of(R)-2-methy-3,5-dihydro-2H-benzo[e][1,4joxathiepine-8-carboxylic acid 1,1- dioxide (intermediate 6) and (S)-2-methy!-3,5-dihydro-2M-benzo[e][1,4]oxathiepme-8-carboxyiic acid 1,1-dioxide (intermediate 7) Racemic 2-methyi-3,5-dihydro-2H-benzo[ej[1,4]oxathiepine-8-carboxyiic acid 1,1 -dioxide was separated by SFC (column: Daicel ChiralPak IG (250x30mm, 10um); mobile phase: [0.1%NH3H2O MEOHj;B%:30%-30%,3.0;85min). The eluent was concentrated to remove most ot the solvent and adjusted to pH-6 with FA. Then the mixture was extracted with DCM (20 mLx2). The combined organic layer was dried with anhydrous N82SO4 and concentrated to afford (R)-2-methyl-3,5-dihydro-2H- benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (35 mg, 0.136 mmol, 44% yield) as a white solid and (S)-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (40 mg, 0.1mmol, 50.00% yield) as a white solid. Stereochemistry was assigned arbitrarily. (R)-2-methyl-3,5-dihydro-2H-benzo[e][1,4joxathiepine-8-carboxylic acid 1,1-dioxide (Intermediate 6): LCMS (ESI) m/z: [M+Na] + = 279.1.Chiral SFC: IG-35״CM״MEOH(DEA)_5_403״ML״T35.M; Rt = 1.729 mins. (S)-2-methyl-3,5-dihydro-2H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (Intermediate 7): LCMS (ESI) m/z: [M+Na] + = 279.1.Chiral SFC: IG-35״CM״MEOH(DEA)3 ״ 40 _ 5 ״ ML״T35.M; Rt = 1.897 mins.
Intermediate 8. 6,7,8,9-Tetrahydrothsepino[3,2-b]pyridine-3-carboxyisc acid 5,5-dioxide OK K *'s: .0: PPh3> DEAD •ci K3PO4, Fd(dibpf)a2 srn DMF, 25 °C, 12 hrs Br N־ THF, 0 °C to RT dioxane / H20, 80 aC، 1 hr Grubbs catslyst DCM, RT.16 hra Steg Step 2 Step 3 Step 4 ؛ C • Pd(OAc)2l dcop K5CO3! CO (15 psi) MS, H2O,100 "C, 4 hrs 'OH Pd/C, H2(15 psi) -s. Oxone -s: 'OH M60H, RT ־N' MeOH, RT Step S Step 8 Step 7 intermedtets 8 Na2S O O N Step 1: Preparation of 2-bromo-5-chtoro-pyridine-3-thiol To a mixture of2-broro-5-chloro-3-fluoro-pyridine (1.3 g, 6.18 mmol, 1 eq) in DMF (20 mL) was added Na2S (482.14 mg, 6.18 mmol, 259.22 pL) in one portion at 25 °C under N2. The mixture was stirred at 25 °C for 12 h. The mixture was poured into (100 mL). To the mixture was added aqueous HCI (2M) to adjust pH = 3. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL x 1), dried with anhydrous N32SO4, filtered and concentrated under vacuum to afford 2-bromo-5-chloro-pyridine-3-thiol (1.2 g, 5.35 mmol, 86.52% yield) as yellow solid.LCMS (ESI) m/z: [79BrM-rHr = 225.8.,H NMR (400 MHz, DMSO-ds) 6 = 8.33 - 8.23 (m, 1H), 8.17 - 8.08 (m, 1H) ppm.
Step 2: Preparation of 2-bromo-3-(but-3-en-1-yithio)-5-chtoropyridme To a mixture of 2-bromo-5-chloro-pyridine-3-thiol (1.2 g, 5.35 mmol) and but-3-en-1 ־ol (385.mg, 5.35 mmol, 459.91 pL) in THF (10 mL) was added PPh3 (2.10 g, 8.02 mmol) followed by DEAD (1. 189 WO 2022/103899 PCT/US2021/058865 g, 8.02 mmol, 1.46 ml) dropwise at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (30 mL x 1), dried with anhydrous N32SO4, filtered and concentrated under vacuum to afford a residue. The residue was purified by silica gel chromatography (Petroleum ether/ Ethyl acetate = 10 /1). The eluent was concentrated to afford 2-bromo-3-(but-3-en-1- ylthio)-5-chloropyridine (1.2 g, 4.31 mmol, 81% yield) as yellow oil. LCMS (ESI) m/z: [79BrM+H]* = 277.9.,H NMR (400 MHz, CDCb) 6 = 8.05 - 7.99 (m, 1H), 7.34 - 7.28 (m, 1H), 5.88 - 5.73 (m, 1H), 5.16 - 5.(m, 2H), 2.99 - 2.86 (m, 2H), 2.48 - 2.35 (m, 2H) ppm.
Step 3: Preparation of 3-(but-3-en-1-yith!o)-5-chtoro-2-vinylpyridine A mixture of 2-bromo-3-(but-3-en-1-ylthio)-5-chloropyridine (860 mg, 3.09 mmol), potassium vinyltrifluoroborate (1.24 g, 9.26 mmol), Pd(dtbpf)C12 (201.19 mg, 308.69 pmol) and K3PO4 (1.97 g, 9.mmol) in dioxane (12 mL) and H2O (3 mL) was stirred at 80 °C for 1 hr under N2. The mixture was poured into H2O (100 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mLx2), dried over anhydrous N32SO4, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by silica gel chromatography (PE - PE / EA = 20 /1). The eluent was concentrated under reduced pressure to afford 3-(but-3-en-1-ylthio)-5-chloro-2-vinylpyridine (510 mg, 2.26 mmol, 73.% yield) as yellow oil. LCMS (ESI) m/z: [M+H]+ = 226.0.1H NMR (400 MHz, CDCb) 6 = 8.36 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.26 - 7.19 (m, 1H), 6.- 6.36 (m, 1H), 5.89 - 5.81 (m, 1H), 5.57 - 5.53 (m, 1H), 5.20 - 5.07 (m, 2H), 2.97 - 2.93 (m, 2H), 2.44 - 2.36 (m, 2H) ppm.
Step 4: Preparation of 3-chioro-6,7-dihydroth!epino[3,2-b]pyridine A mixture of 3-(but-3-en-1-ylthio)-5-ch!oro-2-vinylpyridine (250 mg, 1.11 mmol) and benzylidene- [1,3-bis(2,4,6-trimethylphenyl)imidazoiidin-2-ylidene]-dichloro-ruthemum;tricydohexylphosphane (Grubbs II) (94.0 mg, 0.111 mol) in DCM (12 mL) was stirred at 25 °C for 16 h under N2. The solution was concentrated under vacuum. The residue was purified by silica gel chromatography (PE - PE/EA = 20/1). The eluent was concentrated under reduced pressure to afford 3-chloro-6,7-dihydrothiepino[3,2-b]pyridine (110 mg, 556.44 pmol, 50% yield) as a yellow oil. LCMS (ESI) m/z: [M+Hp = 198.0.1H NMR (400 MHz, CDCb) 6 = 8.40 (d, J = 2.0 Hz, 1H), 7.71 (d, J= 1.6 Hz, 1H), 6.81 -6.71 (m, 1H), 6.- 6.26 (m, 1H), 3.1 Q - 3.05 (m, 2H), 2.88 - 2.81 (m, 2H) Step 5: Preparation of 6,7-dihydrothiepino[3,2-b]pyridine-3-carboxyfic acid A mixture of 3-chloro-6,7-dihydrothiepino[3,2-bjpyridine (50 mg, 0.253 mol), K2CO3 (52.44 mg, 0.379 mol), Pd(OAc)2 (2.84 mg, 12.65 pmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (15.49 mg, 25.29 pmol) and H2O (100 pL) in DMSO (1 mL) was stirred at 100 °C for h under CO (15 psi). The mixture was poured into H2O (10 mL) and extracted with EA (10 mL x 2). The organic phase was discarded. The aqueous phase was acidified with HCI (1M) to pH 3 and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried 190 WO 2022/103899 PCT/US2021/058865 over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 6,7- dihydrothiepino^-bjpyridine-S-carboxylic acid (28 mg, 135.10 pmol, 53.4 % yield) as white solid. LCMS (ESI) m/z: [M+Hp = 207.9.1H NMR (400 MHz, CDCb) 6 = 8.36 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.26 - 7.19 (m, 1H), 6.- 6.36 (m, 1H), 5.89 - 5.81 (m, 1H), 5.57 - 5.53 (m, 1H), 5.20 - 5.07 (m, 2H), 2.97 - 2.93 (m, 2H), 2.44 - 2.36 (m, 2H) ppm.
Step 6: Preparation of 6,7,8,9-tetrahydrothiepino[3,2-f?]pyridine-3~carboxy1ic acid To mixture of 6,7-dihydrothiepino[3,2-bjpyridine-3-carboxylic acid (28 mg, 135.10 pmol) in MeOH (5 mb) was added Pd/C (wet, 50 mg, 10 % purity) at 25 °C. The mixture was purged with H2 for 3 times and stirred at 25 °C for 30 min under H2 (15 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 6,7,8,9-tetrahydrothiepino[3,2-b]pyridine-3-carboxylic acid (23 mg, 109.91 pmol, 81.2 % yield) as white solid.LCMS (ESI) m/z: [M+H]+ = 210.0.1H NMR (400 MHz, DMSO-d6) 5 = 8.81 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 3.23 - 3.17 (m, 2H), 2.88 - 2.78 (m, 2H), 2.11 - 1.96 (m, 2H), 1.76 - 1.62 (m, 2H) ppm.
Step 7: Preparation of 5,5-dioxo-6,7,8,9-tetrahydrothiepino[3,2-f?]pyndine-3-carboxylic acid (Intermediate 8) To a mixture of 6,7,8,9-tetrahydrothiepino[3,2-b]pyridine-3-carboxyiic acid (23 mg, 109.91 pmol) in MeOH (1 ml) and H2O (1 mL) was added Oxone® (67.57 mg, 109.9 pmol) at 25 °C. The mixture was stirred at 25 °C for 4 h. The mixture was quenched with sat. Na2SO3 (20 mL), acidified with HCI (1 M) to pH = 2 and extracted with EA (20 mL x 2). The combined organic layers were washed with brine dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 5,5-dioxo-6,7,8,9- tetrahydrothiepino[3,2-b]pyridine-3-carboxylic acid (18 mg, 74.61 pmol, 68% yield) as white solid. LCMS (ESI) m/z: [M+Hf = 241.9.1H NMR (400 MHz, DMSO-d6) b = 9.14 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.1 Hz, 1H), 3.53 - 3.51 (m, 2H), 3.17 (br d, J = 5.2 Hz, 2H), 2.19-2.13 (m, 2H), 1.82 (br d, J = 3.2 Hz, 2H) ppm.
Intermediate 9: 4,5-dihydro-2iR-benzo[d][1,3]oxathiepine-8-carboxylic acid 1,1-dioxide Step 1 ' ؛ B ־ y ؛ 5 '، 5 ' V'V'8' NaBH4 HS .׳ HO H2O2J « «־ i J ؛ ^ — O --------------------- | ן! / -- Bho' ^Xs^ ENOH,25/0,1hr EtOH, 25׳B0°C, HO X/ X/minStep 2 Step 3 Step 4 C!CH2i, NaHDMF, 0 °C to RTPd(OAc) 2, dopp K2GO3, CO !15 psi) Step 5DMSO, H20,100״C,2hremCPBADCM, RTStep 8intermediate ® 191 WO 2022/103899 PCT/US2021/058865 Step: Preparation of (6-bromobenzo[fc]thiophen-2-yi)boronic acid To a mixture of 6-bromobenzo[6]thiophene (8 g, 37.54 mmol) in THF (80 mb) was added LDA (M, 22.53 mb) dropwise at -70° C under N2. The mixture was stirred at -70° C for 1 hr. Then to the mixture was added triisopropyl borate (8.47 g, 45.05 mmol, 10.36 mb) at -70° C and the mixture was stirred for 1 hr. To the mixture was added H2SO4 (7.36 g, 75.08 mmol, 4.00 mb) at -70° C and the mixture was stirred at 25° C for 1 hr. The mixture was poured into water (300 mb) and extracted with ethyl acetate (200 mLx2). The combined organic phase was washed with brine (200 mbx1), dried with anhydrous NazSO4, filtered and concentrated in vacuum. The residue was triturated by PE / MTBE = 10/ (50 mb). The suspension was filtered. The filter cake was dried under pump to afford (6- bromobenzo[b]thiophen-2-yl)boronic acid (7.3 g, 28.41 mmol, 76% yield) as light yellow solid.1H NMR (400 MHz, DMSO-d6) 6 = 8.58 - 8.53 (m, 2H), 8.28 - 8.24 (m, 1H), 7.96 - 7.93 (m, 1H), 7.88 - 7.84 (m, 1H), 7.54 - 7.46 (m, 1H) ppm.
Step 2: Preparation of 6-bromobenzo[b]thiophen3)2״H)~one To a mixture of (6-bromob®nzo[b]thiophen-2-yi)boromc acid (6.5 g, 25.30 mmol) in EtOH (mb) was added H2O2 (38.35g, 338.24 mmol, 32.50 mb) dropwise at 25° C under N2. The mixture was stirred at 25° C for 1 hr. The mixture was filtered. The filter cake was washed with H2O (50 mb) and dried in vacuum to afford 6-bromobenzo[b]thiophen-2(3H)-one (4.2 g, 18.33 mmol, 72% yield) as brown solid.LCMS (ESI) m/z: [M+Hf =214.8, 216.9.1H NMR (400 MHz, CDCb) 6 = 7.53 - 7.47 (m, 1H), 7.38 - 7.32 (m, 1H), 7.16 (d, J= 8.0 Hz, 1H), 4.06 - 3.84 (m,2H) ppm.
Step 3: Preparation of 2-(4-bromo-2-mercaptophenyi)ethan-1-oi To a mixture of 6-bromobenzo[bjthiophen-2(3H)-one (4.2 g, 18.33 mmol) in EtOH (67 mb) was added NaBH4 (3.47 g,91.67 mmol) in portions at 25° C under N2. The mixture was stirred at 80° C for min. The mixture was cooled to 25° C. To the mixture was added aqueous HCI (1M) slowly to adjust pH=2. The mixture was poured into water (200 mb) and extracted with ethyl acetate (100 mbx2). The combined organic phase was washed with brine (100 mb), dried over anhydrous N32SO4, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 2 /1). The eluent was concentrated to afford 2-(4-bromo-2-mercaptophenyl)ethan-1-ol (3.6 g, 15.44 mmol, 84% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6) 5 = 7.61 (d, J = 2.0 Hz, 1H), 7.24-7.22 (m, 1H), 7.13 (d, J= 8.2 Hz, 1H), 5.58 (s,1H), 4.97 - 4.49 (m, 1H), 3.59-3.57 (m, 2H), 2.71-2.69 (m, 2H).
Step 4: Preparation 8-bromo-4,5-dihydrobenzo[cg[1,3]axathiiepme To a mixture of 2-(4-bromo-2-mercaptophenyl)ethan-1-ol (500 mg, 2.14 mmol ) in DMF (50 mb) was added NaH (257.37mg, 6.43 mmol) in portions at 0° C under N2. The mixture was stirred at 25° C for min. Then to the mixture was added chloro(iodo)methane (416.13 mg, 2.36 mmol, 171 pb) in DMF (mb) dropwise at 0° C under N2. The mixture was stirred at 25° C for 1.5 h. The mixture was poured into sat.NH4CI (10 mb) and extracted with ethyl acetate (10 mbx2). The combined organic phase was washed with brine (10 mb), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was 192 WO 2022/103899 PCT/US2021/058865 purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 10 /1). The eluent was concentrated to afford 8-bromo-4,5-dihydrobenzo[dj[1,3]oxathiepine (50 mg, 0.189 mmol, 9% yield) as yellow oil.LCMS (ESI) m/z: [M+HF =246.2, 248.0.1H NMR (400 MHz, DMSO-d6) 6 = 7.67 - 7.60 (m, 1H), 7.47 - 7.38 (m, 1H), 7.31 - 7.22 (m, 1H), 5.00 - 4.86 (m, 2H), 3.81 -3.67 (m, 2H), 3.12-3.09 (m, 2H) ppm.
Step 5: Preparation of 4,5-dihydrobenzo[d][1,3]oxathiepine-8-carboxylic acid A solution of 8-bromo-4,5-dihydrobenzo[d][1,3]oxathiepine (50 mg, 203.97 pmol), Pd(OAc)2 (4.mg, 20.40 pmol), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (24.98 mg, 40.79 pmol) and K2CO3 (56.38 mg, 0.408 mmol) in DMSO (2 mb) and H2O (0.2 mb) was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (15 psi) at 100° C for 2 h. The mixture was poured into water (20 mb) and extracted with ethyl acetate (10 mb x 2). The organic layer was discarded. To the aqueous phase was added aqueous HCI (1 M) to adjust pH=3. The mixture was extracted with ethyl acetate (10 mb x2). The combined organic phase was washed with brine (10 mb), dried over anhydrous N32SO4, filtered and concentrated in vacuum to afford 4,5- dihydrobenzo[d][1,3]oxathiepine-8-carboxylic acid (40 mg, 190.25 pmol, 93% yield) as yellow solid LCMS (ESI) m/z: [M+HF =211.1.
Step 6: Preparation of 4,5-d!hydro-2H-benzo[dH1,3]oxathiepme-8-carboxyiic acid 1,1-dioxide (intermediate 9) To a mixture of4,5-dihydrobenzo[d][1,3]oxathiepine-8-carboxyiicacid (20 mg, 95.13 pmol) in DCM (1 mb) was added mCPBA (48.28 mg, 237.81 pmol, 85% purity) in portions at 25° C under N2. The mixture was stirred at 25° C for 12 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase column (FA) directly. The eluent was concentrated to remove MeCN. The aqueous phase was lyophilized to afford 4,5-dihydrobenzo[d][1,3]oxathiepine-8-carboxylic acid 1,1-dioxide (20 mg, 82.56 pmol, 86.79% yield) as a white solid. bCMS (ESI) m/z: [M+H2Oj+ =260.0.1H NMR (400 MHz, DMSO-d6) 6 = 8.38 (d, J= 1.6 Hz, 1H), 8.16-8.14 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 4.99 (s, 2H), 4.01-4.00 (m, 2H), 3.42 (s, 2H) ppm.
Intermediate 10: 4,5-dihydro-2Ji1f-benzo[d][1,3]oxathiepine-8-carboxyl!c acid 1,1-dioxide PMBSH. K2CO3 DMF, 80 ,C, 2 hrs THF, 0 eC. '1 hr Step 3 NaBHj, (2 sq) TEA.THF. 30 *C, 5 hrs Stop 4 Stop 2 Pd*OAc)2, ilccp,2HBF4, K2CO3, CO (15 pel) OMSO, HXO, 100 "C, 2؛״s Step 8 Oxone 30 ’C, 2 hrs MsOH, H2O, intermediate 10 Step 6 ، H ؛ UA Step 1: Preparation of4-bromo-2-(4-methoxyphenyl)methylsulfanyl]benzonitrileTo a solution of4-bromo-2-fluoro-benzonitrile (10 g, 50.00 mmol) and (4-methoxyphenyl)methanethiol (7.71 g, 50.00 mmol) in DMF (100 mb) was added C52CO3 (16.29 g, 50. 193 WO 2022/103899 PCT/US2021/058865 mmol), the mixture was stirred at 60 °C 2 h. The reaction mixture was poured into water (1000 mL), the solution was extracted with EA (1000 mL x 3), the combined organic layer was washed with brine (5mL), dried over Na2SO4, filtered and concentrated to give 4-bromo-24(4- methoxyphenyl)methylsulfanynbenzonitriie (13 g, crude) as a white solid.
Step 2: Preparation of [4-bromo-2-[(4-methoxyphenyS)methyisuSfany1]phenyi]methanamine To a solution of 4-bromo-2-[(4-methoxyphenyl)methylsulfanyl]benzonitrile (13 g, 38.90 mmol) in THF (150 mL) was added LiA؛H4 (1.62 g, 42.78 mmol) at 0 °C under N2, the mixture was stirred at 0 °C for 1 hr. To the mixture was poured into water (1.62 g) and 15 % NaOH solution (2.5 mL), the solution was poured into EA (500 mL), the solution was filtered and the filtrate was concentrated to give [4-bromo- 2-[(4-methoxyphenyl)methylsulfany0phenyl]methanamine (13 g, crude) as yellow oil.1H NMR (400 MHz, DMSO-de) 6 = 7.48 - 7.47 (m, 1H), 7.21 - 7.20 (m, 1H), 7.19 - 7.18 (m, 3H), 6.85 - 6.82 (m, 2H), 4.08 (s, 2H), 3.80 - 3.79 (m, 5H) ppm Step 3: Preparation of [2-[[2^ammomethyi)-5-bromo-pheny8]diisulfanyn-4-bromo- phenyi]methanamine A mixture of [4-bromo-2-[(4-methoxyphenyl)methylsulfanyl]phenyl]methanamine (13 g, 38.mmol) in TFA (130 mL) was stirred at 60 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition). The solution was lyophilizated to give aminomethyl)-5-bromo-phenyl]disulfanyl]-4-bromo-phenyljmethanamine (3.5 g, 7.mmol, 19% yield) as a white solid.LCMS (ESI) m/z: [79BrM+HF = 434.81H NMR (400 MHz, DMSO-d6) b = 8.35 (brs, 3H), 7.55 (s, 2H), 7.50 - 7.37 (m, 1H), 4.05 (s, 2H) ppm Step 4: Preparation of 8-bromo-4,5-dihydro-1,4-benzothiazepin-3-one To a solution of aminomethyl)-5-bromo-phenyljdisulfanyl]-4-bromo-phenyl]methanamine (1 g, 2.30 mmol) in THF (15 mL) was added NaBH4 (261.37 mg, 6.91 mmol), the mixture was stirred at 30 °C for 2 h. Then to the solution was added TEA (11.52 mmol, 1.60 mL), 2-chloroacetyl chloride (312.13 mg, 2.76 mmol), the mixture was stirred at 30 °C for 3 h. The reaction mixture was poured into water (1mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (200 mL), dried over N82SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10:1-0:1), the solution was concentrated to give 8- bromo-4,5-dihydro-1,4-benzothiazepin-3-one (300 mg, 871.29 pmol, 38% yield) as a white solid.LCMS (ESI) m/z: pBrM+Hp = 260.01H NMR (400 MHz, DMSO-de) 5 = 7.37 (d, J = 2.0 Hz, 1H), 7.24 - 7.22 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 4.45 (s, 2H), 3.89 (s, 2H) ppm Step 5: Preparation of 3-oxa-4,5-dihydro-1,4~benzothiazepine-8-carboxyl!c acid (Intermediate 10) To a solution of 8-bromo-4,5-dihydro-1,4-benzothiazepin-3-one (280 mg, 1.08 mmol) in DMSO (mL) was added dicyclohexyl(3-dicyclohexylphosphaniumylpropyl)phosphonium;ditetrafluoroborate (66.mg, 108.47 pmol), K2CO (224.88 mg, 1.63 mmol), Pd(OAc)2 (24.35 mg, 108.47 pmol) and H2O (3.91 mg, 216.94 pmol), the mixture was stirred under CO (15 psi) at 100 °C for 2 h. The reaction mixture was 194 WO 2022/103899 PCT/US2021/058865 filtered, the solution was extracted with MTBE (10 mL), the organic layer was discarded. Then the aqueous phase was adjusted to pH = 2 with 1 N HCI, the solution was extracted with EA (50 mLx5), the combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give 3-oxo-4,5-dihydro-1,4-benzothiazepine-8-carboxylic acid (120 mg, 0.487 mmol, 45% yield) as a white solid.LCMS (ESI) m/z: [M+HP = 224.11H NMR (400 MHz, DMSO-d6) 6 = 13.09 - 13.06 (m, 1H), 8.18 (t, J = 6.4 Hz, 1H), 7.64 (d, J= 1.6 Hz, 1H), 7.60 - 7.57 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.45 (d, J = 6.4 Hz, 2H), 3.91 (s, 2H) ppm Step 6: Preparation of 1,1,3-trioxo-4,5-d!hydro-116,4-benzothiazepine-8-carboxyi!c acid To a solution of 3-oxo-4,5-dihydro-1,4-benzothiazepine~8-carboxyiic acid (50 mg, 223.pmol) in MeOH (0.5 mL) and H2O (0.5 mL) was added Oxone (275.37 mg, 447.93 pmol), the mixture was stirred at 30 ° C for 2 h. The reaction mixture was poured into MeOH (5 mL), the solution was filtered and the filtrate was concentrated to give 1,1,3-trioxo-4,5-dihydro-1 A6,4-benzothiazepine-8-carboxylic acid (57 mg, 223.31 pmol, 99.71% yield) as a white solid. intermediate 11.4-(2-methoxyethyi)-3-methyisulfonyi-benzoic acid Stop 1 exone OS ؛ MeOH i H2O, 0-25 *C,12 hra Stop 2 BH3. THF, 0-25 CC, 2 Step 3 ״*■ ho— hra 0-S=0 DOM,30 °C,12 hrs I Step 4 O=S=O I Pd(OAD)2, dccp-2HBF4, K2C03: CO OMSO, #20,100 •c. 3 hrs Step 5 intsrittsritote 11 Step 1: Preparation of2(4-chloro-2-methylsulfany-phenyl)acetic acid. A mixture of 2-(2-bromo-4-chlorophenyl)acetic acid (1 g, 4.01 mmol), Cui (763.36 mg, 4.01 mmol) and DABCO (899.20 mg, 8.02 mmol, 881.57 uL) in DMSO (10 mL) was stirred at 145 °C for 12 h under N2. The reaction mixture was diluted with 1N HCI (300 mL) and filtered. The filtrate was extracted with DCM (300 mLx2). The organic layers were dried over anhydrous NazSO4, filtered and concentrated to afford the residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 1 / 0 to 0 /1). The eluent was concentrated to afford 2-(4-chloro-2-methylsulfanyl-phenyl)acetic acid (1.5 g, crude) as a yellow solid which was used directly to the next step.
Step 2: Preparation of 2-(4-chtoro-2-methylst4fonyl-phenyl)acet!c acid. To a solution of 2-(4-chloro-2-methylsulfanyl-phenyl)acetic acid (500 mg, 2.31 mmol) in MeOH (mL) and H2O (3 mL) was added oxone (4.26 g, 6.92 mmol) in H2O (3 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with sat.Na2SO3 (100 mL) and stirred for min, then extracted with DCM (100 mL x 3). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was purified by reversed phase (0.1 % FA). The eluent was concentrated to afford 2-(4-chloro-2-methylsulfonyl-phenyl)acetic acid (200 mg, 0.8mol, 35% yield) as a white solid. 195 WO 2022/103899 PCT/US2021/058865 LCMS (ESI) m/z: [M+H] + =248.9.1H NMR (400 MHz, DMSO-d6) 8 = 12.62 -12.54 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.78 - 7.76 (m, 1H), 7.55 (d, J= 8.0 Hz, 1H), 4.05 (s, 2H), 3.26 (s, 3H) ppm.
Step 3: Preparation of 2-(4-chtoro-2-methylsulfonyl-phenyl)etharioi. To a solution of 2-(4-chtoro-2-methylsulfonyl-phenyl)acetic acid (200 mg, 804.24 pmoi) in THE (ml) was added a mixture of BH3-M625 (10 M, 402.12 uL) at 0°C. The mixture was stirred at 25 °C for h. The reaction mixture was diluted with 1 N HCI (10 mL) and extracted with DCM (10 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was purified by reversed phase (0.1 % FA). The eluent was concentrated to afford 2-(4-chloro-2- methylsulfonyl-phenyl)ethanol (180 mg, 766.94 pmol, 96% yield) as colorless oil. LCMS (ESI) m/z: [M+H] + =235.0.1H NMR (400 MHz, CDCb) 6 = 8.06 (d, J = 2.4 Hz, 1H), 7.58-7.55 (m, 1H), 7.42 (d, 8.0 Hz, 1H), 3.97- 3.94 (m, 2H), 3.28 - 3.25 (m, 2H), 3.15 (s, 3H) ppm.
Step 4: Preparation of4-chloro-1~(2-methoxyethyl)-2-methylsulfonyi-benzene.To a solution of 2-(4-chloro-2-methylsulfonyl-phenyl)ethanol (80 mg, 0.341 mmol) in DCM (1 mL) was added Ag2O (236.97 mg, 1.02 mmol) and Mel (241.91 mg, 1.70 mmol, 106 uL). The mixture was stirred at 30 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford the residue, which was purified by reversed phase (0.1 % FA). The eluent was concentrated to afford 4-chloro-1-(2-methoxyethyl)-2-methylsulfonyl-benzene (60 mg, 0.241 mmol, 71% yield) as a yellow solid.LCMS (ESI) m/z: [M+H] * =248.9.1H NMR (400 MHz, CDCb) 8 = 8.06 (d, J = 2.4 Hz, 1H), 7.55 - 7.52 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H), 3.70 - 3.67 (m, 2H), 3.33 - 3.29 (m, 5H), 3.15 (s, 3H) ppm.
Step 5: Preparation of 4-(2-methoxyethyi)~3-methylsuifonyl-benzoic acid ((intermediate 11) A mixture of 4-chloro-1-(2-methoxyethyl)-2-methylsulfonyl-benzene (60 mg, 0.241 mmol), K2CO(50.0 mg, 0.362 mmol), dicyclohexyl(3-dicyclohexylphosphaniumylpropyl)phosphonium; ditetrafluoroborate (14.77 mg, 24.12 umol) and Pd(OAc)2 (2.71 mg, 12.06 umol) in DMSO (1 mL) and H2O (0.2 mL) was degassed and purged with CO for 3 times. The mixture was stirred at 100 °C for 3 h under CO (15 psi) atmosphere. The reaction mixture was diluted with MeOH (10 mL) and filtered. The filtrate was concentrated to get the residue. The residue was purified by reversed phase (0.1 % FA). The eluent was concentrated to remove the ACN and lyophilized to afford 4-(2-methoxyethyl)-3- methylsulfonyl-benzoic acid (50 mg, 0.194 mmol, 80% yield) as a white solid.LCMS (ESI) m/z: [M+H] ، =259.0.1H NMR (400 MHz, CDCb) 8 = 8.78 (d, J= 1.6 Hz, 1H), 8.28 - 8.26 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 3.77 - 3.74 (m, 2H), 3.45 - 3.42 (m, 2H), 3.33 (s, 3H), 3.19(s, 3H) ppm. 196 WO 2022/103899 PCT/US2021/058865 Intermediate 12. 4-(2-methoxyethyi)-3-methyisulfonyi-benzoic acid TEA, Boc؟O, DMAPDCM, 0-20 °C, 2 hStep 1 grubbs catalystDCM, 25 °C, 2 hStep 2 Pd/C, H2MeOH, 20 °C, 16 hStepS aq.NaOH THF/H2O, 25 °C, 2 hStep 4 HCI/dloxane °C, 2 hStep 5Intermediate 12 3Q Step 1: Preparation of methyl 3-[aliy!(tert-butoxycarbonyi)suifamoyi]-4-vinyi-benzoate To a solution of methyl 3-(allylsulfamoyl)-4-vinyl-benzoate (1.2 g, 4.27 mmol) (Prepared according to the method in FG-A4366) and DMAP (52.11 mg, 426.55 pmol) in DCM (20 mL) was added TEA (863.24 mg, 8.53 mmol, 1.19 mL) and BoczO (1.86 g, 8.53 mmol, 1.96 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h. It was poured into water (60 mL) and extracted with DCM (40 mLx3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (!SCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethylacetate/Petroleum ethergradient @ 50 mL/min). The fraction was concentrated in vacuum to give methyl 3-[ailyl(tert-butoxycarbonyl)sulfamoyl]-4-vinyi-benzoate (1.5 g, 3.93 mmol, 92% yield) as a yellow oil.1H NMR (400 MHz, DMSO-de) 5 = 8.50 (d, J = 2.0 Hz, 1H), 8.34-8.15 (m, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.23 - 7.00 (m, 1H), 6.01 - 5.86 (m, 2H), 5.75 - 5.61 (m, 1H), 5.39 -5.14 (m, 2H), 4.38 (d, J = 4.8 Hz, 2H), 3.91 (s, 3H), 1.13 (s, 9H) ppm.
Step 2: Preparation of2-(tert-butyl) 8-methyl benzo[f][1,2]thiazepine-2,8(3H)-dicarboxyiate 1,1- dioxide A mixture of methyl 3-[allyl(tert-butoxycarbonyl)sulfamoy0-4-vinyl-benzoate (1.5 g, 3.93 mmol) and benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro- ruthenium;tricyclohexylphosphane (333.85 mg, 393.24 pmol) in DCM (80 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 25 °C for 2 h under N2 atmosphere. It was concentrated to remove DCM. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethylacetate/Petroleum ethergradient @ 50 mL/min). The fraction was concentrated in vacuum to give 2-(tert-butyl) 8-methyl benzo[f][1,2]thiazepine-2,8(3H)-dicarboxylate 1,1-dioxide (1.1 g, 2.77 mmol, 70% yield) as a yellow solid. LCMS (ESI) m/z: [Br7sM+H] ، = 298.1H NMR (400 MHz, DMSO-ds) 6 = 8.43 (d, J= 1.6 Hz, 1H), 8.32-8.17 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 12.8 Hz, 1H), 6.39 -6.18 (m, 1H), 4.95 - 4.57 (m, 2H), 3.92 (s, 3H), 1.11 (s, 9H) ppm.
Step 3: Preparation of 2-(tert-butyl) 8-methyl 4,5-dihydrobenzo[f][1,2]thiazepme-2,8(3H)- dicarboxylate 1,1-dioxide A mixture of 2-(tert-butyl) 8-methyl benzo[f][1,2]thiazepine-2,8(3H)-dicarboxylate 1,1-dioxide (5mg, 1.41 mmol), Pd/C (50 mg, 10% purity) in MeOH (10 mL) was degassed and purged with H2 for times. The mixture was stirred at 20 °C for 16 h under H2 atmosphere. It was filtered and concentrated to give 2-(tert-butyl) 8-methyl 4,5-dihydrobenzo[f|[1,2]thiazepine-2,8(3H)-dicarboxylate 1,1-dioxide (4.1 g, 12.27 mmol, 96% yield) as a yellow oil. 197 WO 2022/103899 PCT/US2021/058865 LCMS (ESI) m/z: [Br79M+H] 300.0 = ؛ 1H NMR (400 MHz, DMSO-ds) 6 = 8.37 (d,J=2.0 Hz, 1H), 8.23-8.11 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 4.17-4.06 (m, 2H), 3.90 (s, 3H), 3.32 - 3.14 (m, 2H), 1.90- 1.53 (m, 2H), 1.22 (s, 9H) ppm.
Step 4: Preparation of 2-tert-butoxycarbonyl-1,1-dioxo-4,5-dihydro-3H-116,2-benzoth؛azep؛r؛e-8- carboxylic acid To a solution of 2-(tert-butyl) 8-methyl 4,5-dihydrobenzo[f][1,2]thiazep!ne-2,8(3H)-dicarboxyiate 1,1-dioxide (250 mg, 0.703 mmol) in THE (2.5 mL) and H2O (2.5 mL) was added LiOH.H2O (118.06 mg, 2.81 mmol). The mixture was stirred at 25 °C for 2 h. It was adjusted to pH=5 by aq.HCI (1 M) and extracted with EA (40 mLx3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give 2-tert-butoxycarbonyl-1,1-dioxo-4,5-dihydro-3H-1A6,2- benzothiazepine-8-carboxylic acid (190 mg, 0. 473 mmol, 67% yield) as a white solid. LCMS (ESI) m/z: [M+Hp = 285.9 Step 5: Preparation of 1,1-dioxo-2,3,4,5-tetrahydro-1 76,2״-benzothiazepine-8-carboxyiic acid (intermediate 12) A mixture of 2-tert-butoxycarbonyl-1,1-dioxo-4,5-dihydro-3H-116,2-benzothiazepine-8-carboxylic acid (180 mg, 0.527 mmol) in HCI/dioxane (4 M, 3 mL) was stirred at 25 °C for 2 h. It was concentrated to remove dioxane to give 1,1-dioxo-2,3,4,5-tetrahydro-1A6,2-benzothiazepine-8-carboxylic acid (130 mg, 0.468 mmol, 89% yield, HCI) as a yellow solid.1H NMR (400 MHz, DMSO-de) 6 = 8.31 (d, J= 1.6 Hz, 1H), 8.05- 8.00 (m, 1H), 7.57- 7.52 (m, 2H), 3.(br s, 2H), 3.22 (br d, J = 3.2 Hz, 2H), 1.91 -1.77 (m, 1H), 1.70 (br s, 2H) ppm.
Intermediate 13. 2-methyl-1,1-dioxo-4,5-dihydro-3H-1 A,6,2-benzothiazepine-8-carboxylic acid chlorosutfonic acid, 120 °C, 24 h 1. SOCi2, 80 °C2. MeOH, 25 °CDIEA, DCM, 25 °C, 2 hStep 1Step 2 Step 3 K3PO4, Pd(dtbpf)CI 2, Dioxane, 60 °C, 16 hStep 4 K2CO3,M0I go o grubbe catalystDMF, 2O’C,3h DCM25°׳c -2hStep 6Step 5 Pd/C, H2 MeOH, 20 °C, 2 h Step? aq.NaOHTHF/HZO, 25 °C, 2 hStep 8intermediate 13 Step 1: Preparation of 4-bromo-3-chiorosulfonyl-benzoic acid A mixture of 4-bromobenzoic acid (10 g, 49.75 mmol) in HSO3CI (86.95 g, 0. 746 mol, 49.7 mL) was stirred at 100 °C for 16 h. The reaction was stirred at 120 °C for another 16 h. It was poured into ice water (400 mL). A precipitate was formed and the mixture was filtered. The filtered cake was dried under vacuum to afford 4-bromo-3-chlorosulfonyl-benzoic acid (11 g, 36.72 mmol, 73% yield) as a gray solid. 198 WO 2022/103899 PCT/US2021/058865 LCMS (ESI) m/z: [Br79M+H]300.0 = ؛ 1H NMR (400 MHz, DMSO-de) 6 = 13.96 (brs, 1H), 8.46 (d, J= 1.6 Hz, 1H), 7.79 - 7.60 (m, 2H) ppm.
Step 2: Preparation of methyl 4-bromo-3-chiorosuifonyl-benzoate To a mixture of 4-bromo-3-chlorosulfonyl-benzoic acid (11 g, 36.72 mmol) in SOCl2 (43.69 g, 367.25 mmol, 26.64 mL) was stirred at 80 °C for 2 h. Then the mixture was concentrated to remove SOClz. MeOH (11 mL) was added. The mixture was stirred at 20 °C for 0.5 hr. it was poured into water (600 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with brine (2mL), dried over N32SO4, filtered and concentrated to give methyl 4-bromo-3-chlorosulfonyl-benzoate (g, crude) as a yellow solid.LCMS (ESI) m/z: [Br79M+Hp = 314.1H NMR (400 MHz, DMSO-de) 5 = 9.31 (brs, 2H), 8.71 - 8.31 (m, 1H), 7.89 - 7.62 (m, 2H), 3.86 (s, 3H).
Step 3: Preparation of methyl 3~(allyisulfamoyl)-4-broma-benzoate To a solution of methyl 4-bromo-3-chlorosulfonyl-benzoate (4 g, 12.76 mmol) and prop-2-en-1- amine (1.31 g, 14.03 mmol, 1.73 mL, HCI) in DCM (40 mL) was added DIEA (6.60 g, 51.03 mmol, 8.mL) at 0 °C. Then then mixture was stirred at 25 °C for 2 h. It was poured into water (100 mL) and extracted with DCM (60 mLx3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethylacetate/Petroleum ethergradient @ 1mL/min). The fraction was concentrated in vacuum to give methyl 3-(allylsulfamoyl)-4-bromo-benzoate (4.1 g, 12.27 mmol, 96% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 6 = 8.51 - 8.42 (m, 1H), 8.29 (brs, 1H), 8.01 (d, J = 0.8 Hz, 2H), 5.77 - 5.52 (m, 1H), 5.17 - 5.06 (m, 1H), 5.03 - 4.93 (m, 1H), 3.89 (s, 3H), 3.57 (br d, J = 4.8 Hz, 2H) ppm.
Step 4: Preparation of methyl 3-(allylsulfamoyl)-4-vmyl-benzoate A mixture of methyl 3-(allylsulfamoyl)-4-bromo-benzoate (3.1 g, 9.28 mmol), potassium; trifluoro(vinyl)boranuide (6.21 g, 46.38 mmol), ditert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (604.6 mg, 0.928 mmol), and K3PO4 (5.91 g, 27.8 mmol) in dioxane (30 mL) and H2O (6 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 60 °C for 16 h under Natmosphere. It was poured into water (100 mL) and extracted with EA (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethylacetate/Petroleum ethergradient @ 80 mL/min). The fraction was concentrated in vacuum to give methyl 3-(allylsulfamoyl)-4-vinyl-benzoate (1.5 g, 5.33 mmol, 57% yield) as a white solid. LCMS (ESI) m/z: [M+Hp = 282.,H NMR (400 MHz, CDCb) 6 = 8.62 (d,J=1.6 Hz, 1H), 8.29-8.11 (m, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.- 7.47 (m, 1H), 5.92 - 5.77 (m, 1H), 5.73 - 5.53 (m, 2H), 5.22 - 4.97 (m, 2H), 4.84 - 4.57 (m, 1H), 3.69 - 3.41 (m, 2H) ppm. 199 WO 2022/103899 PCT/US2021/058865 Step 5: Preparation of methyl 3-[allyi(methyl)stdfamoyl]-4-vinyi-benzoate To a solution of methyl 3-(a ؛ly ؛sulfamoy4-( ؛-vinyl-benzoate (200 mg, 0.711 mmol) and K2CO(196.5 mg, 1.42 mmol) in DMF (2 mL) was added Mel (201.81 mg, 1.42 mmol, 88.5 pL). The mixture was stirred at 20 =C for 3 h. It was poured into water (60 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (20 mL) and then dried over N32SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethylacetate/Petroleum ethergradient @ 50 mL/min). The fraction was concentrated in vacuum to give methyl 3-[allyl(methyl)sulfamoyl]-4-vinyl-benzoate (190 mg, 0.6mmol, 90% yield) as a yellow oil. LCMS (ESI) m/z: [M+HF = 296.1H NMR (400 MHz, CDCb) 6 = 8.56 (d, 1.6 Hz, 1H), 8.26-8.09 (m, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.67- 7.53 (m, 1H), 5.88 - 5.77 (m, 1H), 5.76 - 5.64 (m, 1H), 5.59 - 5.50 (m, 1H), 5.27 - 5.16 (m, 2H), 3.96 (s, 3H), 3.75 (d, J = 6.4 Hz, 2H), 2.75 (s, 3H) ppm.
Step 6: Preparation of methyl 2-methyM,1-d!oxo-3H-1 H 6,2-benzothiazepine-8-carboxyiate A mixture of methyl 3-[ailyl(methyl)sulfamoyl]-4-vinyl-benzoate (190 mg, 0.643 mmol) and benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro- ruthenium;tricyciohexyiphosphane (54.61 mg, 64.33 pmol) in DCM 10 mL) was degassed and purged with N2 for 3x. The mixture was stirred at 25 °C for 2 h nder N2 atmosphere. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of -50% Ethylacetate/Petroleum ethergradient @ 30 mL/min). The fraction was concentrated in vacuum to give methyl 2-methyl-1,1-dioxo-3H-1A6,2-benzothiazepme-8-carboxylate (130 mg, 0.486 mmol, 76% yield) as a white solid.LCMS (ESI) m/z: [M+HF = 268.1H NMR (400 MHz, DMSO-d6) 6 = 8.38 (d, J = 2.0 Hz, 1H), 8.26-8.10 (m, 1H), 7.78 (d, J = 8.4 Hz, 1H), 6.72 (brd, J = 13.2 z, 1H), 6.31 - 5.96 (m, 1H), 4.45 -4.17 (m, 2H), 3.90 (s, 3H), 2.55 (s, 3H) ppm.
Step 7: Preparation of methyl 2-methyM,1-d!oxo-4,5-dihydro-3H-1 26,2-benzothiazepine-8- carboxylate A mixture of methyl 2-methyl-1,1-dioxo-3H-1A6,2-benzothiazepine-8-carboxylate (130 mg, 0.4mmol), Pd/C (13 mg, 10% purity) in MeOH (4 mL) was degassed and purged with H2 for 3 times. Then the mixture was stirred at 20 °C for 2 h under H2 atmosphere. It was filtered and concentrated to give methyl 2-methyl-1,1-dioxo-4,5-dihydro-3H-1A6,2-benzothiazepine-8-carboxylate (110 mg, 0.408 mmol, 84% yield) as a white solid. LCMS (ESI) m/z: [M+HF = 27Q.1H NMR (400 MHz, CDCb) 5 = 8.56 (d, J = 2.0 Hz, 1H), 8.17 - 8.03 (m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 3.(s, 3H), 3.92 - 3.59 (m, 2H), 3.45 - 3.23 (m, 2H), 2.65 (s, 3H), 1.91 -1.80 (m, 3H) ppm.
Step 8: Preparation of 2-methyl-1,1-dioxo-4,5-dihydro-3H-1 1 6,2-benzothiazepine-8~carboxy1ic acid (Intermediate 13) To a solution of methyl 2-methyl-1,1-dioxo-4,5-dihydro-3H-1A6,2-benzothiazepine-8-carboxylate (110 mg, 0.408 mmol) in THF (1 mL) and H2O (1 mL) was added LIOH.H2O (68.56 mg, 1.63 mmol). The 200 WO 2022/103899 PCT/US2021/058865 mixture was stirred at 25 °C for 2 h. It was adjusted to PH^S by aq.HCI (1 M) and extracted with EA (mLx3), The combined organic layers were washed with brine (20 mL) and then dried over N32SO4, filtered and concetrated to give 2-methyl-1,1-dioxo-4,5-dihydro-3H-1A6,2-benzothiazepine-8-carboxylic acid (80 mg, 0.313 mmol, 77% yield) as a white solid.LCMS (ESI) m/z: [M+H]* = 519.21H NMR (400 MHz, DMSO-d6) 6 = 8.27 (d, 1.6 Hz, 1H), 8.14-8.01 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H),3.75 - 3.55 (m, 2H), 3.23 (br s, 3H), 2.55 (s, 3H), 1.83 - 1.71 (m, 2H) ppm.
Intermediate 14. 4-(d!fiuoromethyl)-3-(methyisu!fonyl)benzoic acid DAST DCM, 25 °C,1 hr Step 1 Step 2 DMBCO Cui --------------- £ DM30,145 °C, 12 hrs Step 3 Oxone MeOH / H2O,0 - 25 °C, 12 hrs Step 4 intermediate 14 Step 1: Preparation of methyl 3-bromo-4~(difkioromethyl)benzoate. To a solution of methyl 3-bromo-4-formylbenzoate (300 mg, 1.23 mmol) in DCM (3 mb) was added DAST (596.87 mg, 3.70 mmol, 489.24 uL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with sat.NaHCO3 (20 mb) and extracted with DCM (20 mb). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 1 / 0 to 3 /1). The eluent was concentrated to afford methyl 3-bromo-4-(difluoromethyl)benzoate (190 mg, 716.84 pmol, 58% yield) as yellow oil.1H NMR (400 MHz, CDCb) 6 = 8.28 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0Hz, 1H), 7.06 - 6.(m, 1H), 3.96 (s, 3H) ppm.
Step 2: Preparation of 3-bromo-4-(difiuoromethyl)benzolc acid. To a solution of methyl 3-bromo-4-(difluoromethyl)benzoate (90 mg, 339.56 pmol) in THE / MeOH / H2O = 2/1/1 (1 mb) was added NaOH (27.16 mg, 679.11 pmol). The mixture was stirred at 30 °C for h. The reaction mixture was diluted with 1N HCI (10 mb) and extracted with DCM (10 mb x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to afford 3-bromo- 4-(d!fluoromethyl)benzoic acid (70 mg, 278.86 pmol, 82% yield) as yellow oil which was used directly to the next step. 201 WO 2022/103899 PCT/US2021/058865 Step 3: Preparation of 4-(d!fiuoromethyl)-3-methylsulfanyl-benzoic acid A mixture of 3-bromo-4-(d!f!uoromethyl)benzoic acid (50 mg, 0.199 mmol), DABCO (44.68 mg, 0.398 mmol, 44 uL) and Cui (37.93 mg, 0.199 mmol) in DMSO (0.5 ml) was stirred at 145 °C for 12 h. To the mixture was added 1N HCI to adjust the pH = 5. The mixture was filtered. The filtrate was concentrated to get the residue. The residue was purified by reversed phase (0.1 % FA). The eluent was concentrated to afford 4-(difluoromethyi)-3-methylsulfanyi-benzoic acid (30 mg, 0.137 mmol, 69% yield) as a yellow solid.LCMS (ESI) m/z: M+H] + =218.91H NMR (400 MHz, CDCI3) 6 = 8.10 (s, 1H), 8.02 (d,J-8.4 Hz, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.15- 6.87(m, 1H), 2.58 (s, 3H) ppm.
Step 4: Preparation of 4-(difSuoromethyl)-3-methylsulfonyl-benzoic acid (Intermediate 14) To a solution of 4-(difluoromethyl)-3-methyisulfanyl-benzoic acid (30 mg, 137.48 pmol) in MeOH (0.5 mb) was added a mixture of Oxone (169.03 mg, 274.95 pmol) in H2O (0.5 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford the residue. The residue was purified by reversed phase (0.1% FA). The eluent was concentrated to afford 4-(difluoromethyl)-3-(methylsulfonyl)benzoic acid (20 mg, 79.9 pmol, 58% yield) as a white solid. LCMS (ESI) m/z: [M+H] * =250.9.
Intermediate 15. 6-Methyl-5-(methylsulfonyl)mcotimc acid Step 1: Preparation of 6-methyl-5-(methylthio)nicotin!c acid To a solution of methyl 5-fluoro-6-methyl-pyridine-3-carboxylate (300 mg, 1.77 mmol) in DMF (mL) was added sodium thiomethoxide (320.30 mg, 1.95 mmol). The mixture was stirred at 100 °C for h. The reaction mixture was quenched with HCI (1 M) (40 mL) and extracted with EA/MeOH=15/1(mLx5), The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get residue. The residue was purified by reversed-phase HPLC (0.1% FA condition). The solution was concentrated under reduced pressure to remove MeCN and then lyophilized to afford 6- methyl-5-(methylthio)nicotinic acid (200 mg, 1.09 mmol, 62% yield) as a yellow solid. LCMS (ESI) m/z: [M+Hf= 183.9.1H NMR (400 MHz, DMSO-d6) 6 = 14.14 - 12.40 (m, 1H), 8.69 (d, J= 1.6 Hz, 1H), 7.94 (d, 0=2.0 Hz, 1H), 2.55 (s, 3H), 2.50 (s, 3H) ppm.
Step 2: Preparation of 6-methyF5-(methylsuifony؛)nicotin؛c acid (intermediate 15) To a solution of 6-methyl-5-(methylthio)nicotinic acid (30 mg, 163.73 pmol) in MeOH (1 mL) was added Oxone® (150.98 mg, 0.246 mmol) and H2O (1 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was dissolved with DMSO (5 mL) and then filtered to get the filtrate. The filtrate was purified by reversed-phase HPLC (0.1% FA condition). The solution was concentrated under reduced 202 WO 2022/103899 PCT/US2021/058865 3Q pressure to remove MeCN and then lyophilized to obtain 6-methyl-5-(methylsulfony5)nicotinic acid (15 mg, 67.8 pmoi, 41% yield) as white solid.LCMS (ESI) m/z: [M+H]216.1 ؛.1H NMR (400 MHz, DMSO-de) 6 = 15.43 - 11.63 (m, 1H), 9.17 (d, J = 2.0 Hz, 1H), 8.61 (d, J = 2 0 Hz,1H), 3.36 (s, 3H), 2.90 (s, 3H) ppm.
Intermediate 16. 3-cbioro~4-methyl-5-methy1suifony1-benzoic acid Na gSO3, NaHCOg, NaOHH2O, 80-110 °C, 13 hrsStep 2 i.intermediate 16 Step 1: Preparation of 3-chioro-5-chlorosuifonyl~4-methylbenzoic acid A mixture of 3-chloro-4-methylbenzoic acid (1 g, 5.86 mmol) in chlorosulfonic acid (10.25 g, 87.mmol, 5.85 mb) was stirred at 120 °C for 12 h. The reaction mixture was added to H2O (20 mb) at 0 °C. White solid was precipitated out from the mixture. The solid was collected by filtration and dried under reduced pressure to afford 3-chloro-5-chlorosulfonyl-4-methylbenzoic acid (1.2 g, 4.46 mmol, 76% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 8 = 8.30 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 2.63(s, 3H) ppm.
Step 2: Preparation of 3-chioro-4-methy!~5-methyisulfonyi-benzoic acid (Intermediate 16) To a solution ofNazSO- (140.51 mg, 1.11 mmol) and NaHCO: (280.97 mg, 3.34 mmol, 130.uL) in H2O (1.2 mb) was added 3-chloro-5-chlorosulfonyl-4-methylbenzoic acid (300 mg, 1.11 mmol) at °C. The mixture was stirred at 80 °C for 1 hr. Then 2-bromoacetic acid (309.8 mg, 2.23 mmol, 161 pb) and NaOH (89.19 mg, 2.23 mmol) were added and the mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with H2O (10 mb), then added 1 N HOI to adjust the pH=3. The white solid was precipitated out from the mixture. The solid was collected by filtration and dried under reduced pressure to afford 3-ch!oro-4-methyl-5-methylsulfonyl-benzoic acid (120 mg, 0.483 mmol, 43% yield) as a white solid.bCMS (ESI) m/z: [M+H]+ =248.1H NMR (400 MHz, DMSO-d6) 6 = 8.41 (d, J = 1.6 Hz, 1H), 8.21 (d, J= 1.6 Hz, 1H), 3.32 (s, 3H), 2.74 (s, 3H) ppm.
Intermediate 17. 4-Chtoro-34luoro-5-methyisuifonyi-benzoic acid oxoneMeOH, h20°C, 12 hrsStep 2F intermediate 17 203 WO 2022/103899 PCT/US2021/058865 Step 1: Preparation of4-chloro-3-fluoro-5-methylsulfanyl-benzoic acidA mixture of methyl 3-bromo-4-chloro-5-fluoro-benzoate (200 mg, 747.72 pmol), Cui (142.40 mg, 747.72 pmol) and DABCO (167.8 mg, 1.50 mmol, 164 pL) in DMSO (2 mL) was stirred at 145 °C for 12 h under N2. The reaction mixture was filtered. The filtrate was purified by reversed-phase HPLC (0.1% FA condition). The desired fraction was lyophilized to give 4-chloro-3-fluoro-5-methylsulfanyl-benzoic acid (90 mg, 0.371 mmol, 50% yield) as a white solid.LCMS (ESI) m/z: [M+H]* = 220.9.1H NMR (400 MHz, DMSO-d6) 6 = 7.66 - 7.56 (m, 2H), 2.59 (s, 3H) ppm.
Step 2: Preparation of 4-chlaro-34!uoro-5-methyisulfonyi-benzoic acid (Intermediate 17) To a solution of4-chloro-3-fluoro-5-methylsulfanyl-benzoic acid (90 mg, 0.408 mmol) in H2O (mL) and MeOH (2 mL) was added Oxone® (501.5 mg, 0.816 mmol). The reaction was stirred at 20 °C for 12 h under N2. To the mixture was added saturated aqueous N82SO3 (5 mL). The mixture was extracted with EA (5 mL x 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give 4-chloro-3-fluoro-5-methylsuifonyi-benzoic acid (40 mg, 0.1mmol, 39% yield) as a white solid.LCMS (ESI) m/z: M+HF- = 252.9.1H NMR (400 MHz, DMSO-d6) 6 = 8.35 (s, 1H), 8.21 - 8.19 (m, 1H), 3.45 (s, 3H) ppm.
Intermediate 18. tert-Butyl ((2-chloro-1,6-naphthyridm-7-yl)methyl)carbamate Step 1 Fd(OAc)2; (0-M6Ph)3» Et3N, DMF Step 3 Pd(dppf)C!2CH2CI2 Zn, ZnCN2 DMA Step 4 .Cl DIBAL-H, DCM, -70° C Step 7 Intermediate 18 Step 5 Step 6 Step2 Step 1. Preparation of 2-bromo-5-iodo-pyridin-4-amine NIS (93.6 g, 416 mmol) was added to a solution of 2-bromopyridin-4-amine (60 g, 347 mmol) in MeCN (1.5 L) at 80°C. The reaction mixture was stirred at 80 CC for 36 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with saturated Na2SO(1.5 L) and extracted with EA (1.5 L x 2). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 20:3) and concentrated under reduced pressure affording 2-bromo-5-iodo-pyridin-4-amine (65 g, 217 mmol) as a light-yellow solid.1H NMR (400 MHz, CDCb) 6 = 8.31 (s, 1H), 6.79 (s, 1H), 4.75 (brs, 2H) ppm.
Step 2. Preparation of ethyi-3-(4-amino-6-bromo-3~pyridyi)prop-2-erioate Ethyl prop-2-enoate (45.1 mL, 415 mmol), Et3N (43.3 mL, 311 mmol), Pd(OAc)2 (2.3 g, 10.mmol), and tris-o-tolyiphosphane (6.3 g, 20.7 mmol) was added to a solution of 2-bromo-5-iodo-pyridin-4- 204 WO 2022/103899 PCT/US2021/058865 amine (62 g, 207 mmol) in DMF (620 mL). The mixture was stirred at 10Q°C for 3 h. The reaction mixture was diluted with water (4 L) and extracted with EA (2 L x 2). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 20:3) and concentrated under reduced pressure affording ethyl-3-(4-amino-6-bromo-3-pyridyl)prop-2-enoate (50 g, 170 mmol) as a light yellow solid.LCMS (ESI) m/z: [79BrM+H]+ = 271.1.1H NMR (400 MHz, DMSO-d6) 6 = 8.23 (s, 1H), 7.73 (d, J = 16.0 Hz, 1H), 6.90 - 6.67 (m, 3H), 6.52 (d, J = 16.0 Hz, 1H), 4.18 (d, J = 7.2 Hz, 2H), 1.25 (d, J = 7.2 Hz, 3H) ppm.
Step 3. Preparation of 7-bromo-1,6-naphthyridin-2(1H)-one Sodium thiomethoxide (24.2 mb, 380 mmol) was added to a solution of ethyl-3-(4-amino-6- bromo-3-pyridyl)prop-2-enoate (40 g, 148 mmol) in EtOH (200 mL). The reaction mixture was stirred at °C for 2 h. The reaction mixture was diluted with water (400 mL) and then neutralized with 1N HCi to pH = 7.0. The solid was filtered and the filter cake was washed with water (50 mL). The filter cake was concentrated under reduced pressure affording 7-bromo-1,6-naphthyridin-2(1 H)-one (22 g, 96.8 mmol) as an off-white solid.LCMS (ESI) m/z: [79BrM+H]+ = 224.9. 1H NMR (400 MHz, DMSO-d6) 6 = 12.08 (brs, 1H), 8.65 (s, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.36 (s, 1H), 6.62 (d,Jj= 9.6 Hz, 1H) ppm.
Step 4. Preparation of 2-oxo-1,2-dihydro-1,6-naphthyridme-7-carbomtrile Zinc powder (406.80 mg, 6.22 mmol) was added to a solution of 7-bromo-1,6-oaphthyridm- 2(1H)-one (7 g, 31.1 mmol), Zn(CN)2 (3.95 mL, 62.2 mmol), and Pd(dppf)CI2CH2C 5.08) 2؛ g, 6.22 mmol) in DMA (140 mL). The reaction mixture was degassed and purged with N2 three times then the mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM/isopropanol (v/v=3:1) (150 mLx2). The combined organic layers were filtered, washed with brine (200 mL), dried over N82SO4, filtered , and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=1:1) and concentrated under reduced pressure affording 2-oxo- 1,2-dihydro-1,6-naphthyridine-7-carbonitrile (3 g, 17.5 mmol) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 6 = 12.37 (brs, 1H), 8.97 (s, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.67 (s, 1H), 6.77 (d, J = 9.6 Hz, 1H) ppm.
Step 5. Preparation 2-chloro-1,6-naphthyndsne-7-carbonitnfe A mixture of 2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (3.0 g, 17.5 mmol) and POCls (mL, 323 mmol) was stirred at 80°C for 2 h. The reaction mixture was poured into H2O (2 L) and adjusted to pH = 7 with NaHCO3. The solution was extracted with EA (1.5 L x 2), the combined organic layers were washed with brine (2 L), dried over N32SO4, filtered, and concentrated under reduced pressure to afford 2-chloro-1,6-naphthyridine-7-carbonitrile (1.1 g, 5.76 mmol) as a brown solid. LCMS (ESI) m/z: [M+H]+ = 190.1. 205 WO 2022/103899 PCT/US2021/058865 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 (d, J = 0.8 Hz, 1H), 8.79 (d, J = 0.8 Hz, 1H), 8.69 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H) ppm.
Step 6. Preparation of(2-chloro-1,6-naphthyridin-7-yl)methanamineTo a solution of 2-chloro-1,6-naphthyridine-7-carbonitrile (25 g, 131.86 mmol) in DCM (1000 mL) was added DIBAL-H (1 M, 329.64 mL, 2.5 eq) dropwise at -70 °C under N2. The reaction mixture was stirred at -70° C for 2 h. The reaction mixture was quenched with water (500 mL) and sat. potassium sodium tartrate (1500 mL) and stirred for an additional 30 min. The mixture was extracted with DCM:MeOH=10:1 (6000 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give (2-chloro-1,6-naphthyridin-7-yl)methanamine (51 g, crude) as a brown solid, which was used for the next step directly. LCMS (ESI) m/z: [35CIM+H]+ =194.2 Step 7: Preparation of tert-butyl ((2-chloro~1,6-naphthyrid!n-7-yi)methyl)carbamate (intermediate 18) To a solution of (2-chioro~1,6~naphthyndm-7-yl)methanamine(51 g, 263.4 mmol) in DCM (1500 mL) was added (Boc)2O (172.45 g, 790.16 mmol) and DIEA (102.12 g, 790.16 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (1500 mL) and then filtered. The filtrate was extracted with DCM (1000 mL x 3). The combined organic layers were washed with brine (1500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SIO2, Petroleum ether/Ethyl acetate=10/1 to 2/1 to 1/3) and the eluent was concentrated under reduced pressure to ferf-butyl ((2-chloro-1,6-naphthyridin-7- yl)methyl)carbamate (21 g, 64.34 mmol, 24% yield) as a light yellow solid.LCMS (ESI) m/z: [M+H]+ =293.9.1H NMR (400 MHz, DMSO-d6) 6=9.37 (s, 1H), 8.62 (d, J= 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.58- 7.53 (m, 2H), 4.39 (d, J = 6.4 Hz, 2H), 4.20 - 4.25 (m, 2H), 1.41 (s, 9H) ppm.
Intermediate 19: [2-[6-(2,2-difSuorocydopropyl)-2-pyr!dyl]-1,6-naphthyridm-7-yl]methanamine Step 1 Step 2 Step 3 Step 4 Step 1: Preparation of2-bromo-6-2,2-difluorocyclopropyl)pyridineTo a mixture of 2-Bromo-6-ethenylpyridine (500 mg, 2.72 mmol) and Nai (81.45 mg, 0.543 mmol) in THF (4 mL) was added a solution of TMSCF3 (1.55 g, 10.87 mmol) in THF (1 mL) over 1 h at 70 °C under N2. The mixture was stirred at 70 °C for 1 h under N2. The residue was purified by silica gel 206 WO 2022/103899 PCT/US2021/058865 chromatography (PE - PE / EA = 50 /1), The eluent was concentrated under reduced pressure to afford 2-bromo-6-(2,2-d!fluorocyclopropyl)pyridine (570 mg, 2.44 mmol, 90% yield) as yellow oil.LCMS (ESI) m/z: [M+Hp = 233.9.1H NMR (400 MHz, CDCb) 6 = 7.52 - 7.48 (m, 1H), 7.39 - 7.37 (m, 1H), 7.19 (d, 7.6 Hz, 1H), 2.95 -2.84 (m, 1H), 2.21 -2.12 (m, 1H), 1.89- 1.83 (m, 1H) ppm.
Step 2: Preparation of [6-(2,2-difiuorocyclopropyi)-2-pyridyi]-trimethy1stannane A mixture of2-bromo-6-(2,2-difluorocyclopropyl)pyridine (100 mg, 427.28 pmol), HEXAMETHYLDITIN (279.97 mg, 854.55 pmol, 177.20 uL) and Pd(PPh3)4 (49.37 mg, 42.73 pmol) in dioxane (2 mL) was stirred at 100 °C for 2 h under N2. The mixture was filtered and concentrated under reduced pressure to afford [6-(2,2-d!fluorocyclopropyl)-2-pyridyl]-trimethylstannane (170 mg, crude) as brown oil.LCMS (ESI) m/z: [M+Hp = 320.1.
Step 3: Preparation of tert-butyi Af-[[2-[6-(2,2-difluorocycSopropyl)-2-pyridyl]-1,6-naphthyridin-7- yl]methyi]carbamate A mixture oftert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (50 mg, 170.21 pmol), [6-(2,2-difluorocyclopropyi)-2-pyridy0 ־trimethyistannane (163 mg, 0.511 mmol) and Pd(PPh3)2CI2 (11.mg, 17.02 pmol) in dioxane (1 mL) was stirred at 100 °C for 16 h under N2. The mixture was poured into sat. KF (10 mL) and stirred at 20 °C for 30 min. The mixture was extracted with EA (10 mL x3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by silica gel chromatography (PE / EA /1 - EA). The eluent was concentrated under reduced pressure to afford fert-butyl A/-[[2-[6-(2,2- difiuorocydopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]carbamate (30 mg, 72.74 pmol, 43% yield) as yellow solid. LCMS (ESI) m/z: [M+Hp = 413.3.
Step 4: Preparation of [2-[6-(2,2-difiuorocyctopropyl)-2-pyridyH-1,6-naphthyridin-7-yl]methanamine (Intermediate 19) To a mixture oftert-butyl A/-[[2-[6-(2,2-difluorocydopropyl)-2-pyridyl]-1,6-naphthyridin-7- yl]methyl]carbamate (30 mg, 72.74 pmol) in DCM (1 mL) was added TEA (462 mg, 4.05 mmol, 0.3 mL) at CC. The mixture was stirred at 30 °C for 1 hr. The mixture was concentrated under reduced pressure to afford [2-[6-(2,2-difluorocyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine (31 mg, 72.71 pmol, 100% yield, TEA salt) as yellow solid. LCMS (ESI) m/z: [M+Hp = 313.2. 207 WO 2022/103899 PCT/US2021/058865 Intermediate 20. (2-(2-(2,2-difluorocyctopropy0pynmidin-4-yl)-1,6-naphthyridin-7- yOmethanammemate F MegAI, NH4CI«״ F ;toluene, 0-80"0, h NH« B ؛ j .......................................EtOH, K2CO3, 25-7 °C, 6h oxaly chloride, DMF -------------------------gar.DCM, 0-25 °C, 20 min Step 1 Step 3 trimethyl(trimethylstanny!)stennanePd(PPh 3)4،<- ja ------------------- : ------ ؛ ------------------dioxane, 25-100 °C, 2 h Step 4 TFADCM,°C,min Step 5 Step 3 Step 1: Preparation of 2,2-difluorocyclopropanecarboximidamideTo a mixture of NH4CI (6.88 g, 128.59 mmol) in toluene (50 mL) was added a solution of AI(CH3)(2 M, 64.29 mL) at 0 °C. Then the mixture was stirred at 25°C for 1 hr. To the solution was added methyl 2,2-difluorocydopropanecarboxylate (3.5 g, 25.72 mmol) at 0°C and then the solution was stirred at 80°C for 12 h. A heavy white solid formed. The reaction mixture was cooled to 0 °C. MeOH (50 mL) was added and then stirred for 10 min. The mixture was filtered. The filtrate was concentrated in vacuum to give 2,2-difluorocyciopropanecarboximidamide (3 g, crude) as a white solid which was used directly.
Step 2: Preparation of 2-(2,2-difiuorocydopropyl)pyrimidm-4-ol To a mixture of 2,2-difluorocyciopropanecarboximidamide (3.00 g, 24.97 mmol) in EtOH (40 mL) was added K2CO3 (6.90g, 49.94 mmol) in one portion at 25°C under N2. The mixture was stirred at 25 °C for 10 min, then (E)-ethyl 3-ethoxyacrylate (1.2 g, 8.32 mmol, 1.20 mL) was added at 25 °C. The mixture was stirred at 75°C for 6 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The mixture was purified by silica gel chromatography (DCM / MeOH = 20 /1). The eluent was concentrated to afford 2-(2,2-difluorocyclopropyl)pyrimidin-4-ol (500 mg, 2.90 mmol, 35% yield) as white solid.LCMS (ESI) m/z: =173.2.1H NMR (400 MHz, CDCb) 8 = 8.04 - 7.95 (m, 1H), 6.43 - 6.35 (m, 1H), 2.84 - 2.69 (m, 1H), 2.51 - 2.(m, 1H), 2.00 - 1.88 (m, 1H) ppm.
Step 3: Preparation of 4-chloro-2-(2,2-difiuorocydopropyi)pynm!dme To a mixture of 2-(2,2-difluorocyclopropyl)pyrimidin-4-ol (350 mg, 2.03 mmol) and DMF (14.9 mg, 0.203 mmol, 15.6 uL) in DCM (6 mL) was added oxalyl chloride (516 mg, 4.07 mmol, 356 pL) in one 208 WO 2022/103899 PCT/US2021/058865 portion at 0 °C under N2. The mixture was stirred at 25 °C for 20 min. The mixture was added to sat. NaHCOs (50 mb) at 0 °C. The aqueous phase was extracted with DCM (50 mb x 2). The combined organic phase was washed with brine (50mLx1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by siiica gei chromatography (PE/EA — 10/1). The eluent was concentrated to afford 4-chloro-2-(2,2-difluorocyclopropyl)pyrimidine (150 mg, 0.787 mmol, 39% yield) as light yellow oil.LCMS (ESI) m/z: [M+H]* =190.9, 192.9.
Step 4: Preparation of 2-(2,2-dif!uorocycioprapyl)-4-(tributytetannyl)pyrimidine To a mixture of 4-chloro-2-(2,2-difluorocyclopropyl)pyrimidine (100 mg, 0.525 mmol) and trimethyl(trimethylstannyl)stannane (343.8 mg, 1.05 mmol, 218 pL) in dioxane (2 mb) was added Pd(PPh3)4(60.63 mg, 52.47 pmol) in one portion at 25°C under N2. The mixture was stirred at 100 °C for h. The mixture was poured into water (10 mb) and extracted with ethyl acetate (10 mbx2). The combined organic phase was washed with brine (10 mb x 1), dried with anhydrous N32SO4, filtered and concentrated in vacuum to afford 2-(2,2-difluorocyclopropyl)-4-(tributylstannyl)pyrimidine (150 mg, crude) as yellow oil.LCMS (ESI) m/z: M+HF- =320.9.
Step 5: Preparation tert-buty ((2-(2-(2,2-difluorocyctopropyi)pyr!midin-4-yi)-1,6-naphthyndin-7- yi)methyi)carbamate To a mixture of 2-(2i2-difluorocyclopropyl)-4-(tributylstannyl)pyrimidine (147 mg, 0.460 mmol) and fert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (90 mg, 0,306 mmol) in dioxane (2 mb) was added Pd(PPh3)2CI2 (21.51 mg, 30.64 pmol) in one portion at 25°C under N2. The mixture was stirred at 100 °C for 12 h. The mixture was poured into water (30 mb) and extracted with ethyl acetate (20 mb x 2). The combined organic phase was washed with brine (20 mb x 1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (PE / EA = 3 / 1). The eluent was concentrated to afford tert-butyl ((2-(2-(2,2-difluorocyclopropyl)pyrimidin-4-yl)-1 ,6- naphthyridin-7-yl)methyl)carbamate (90 mg, 0.218 mmol, 71% yield) as yellow solid. bCMS (ESI) m/z: [M+Hj+ =414.0.1H NMR (400 MHz, DMSO-d6) 6 = 9.50 - 9.43 (m, 1H), 9.08 - 9.01 (m, 1H), 8.84 - 8.78 (m, 1H), 8.73 - 8.67 (m, 1H), 8.50 - 8.44 (m, 1H), 7.86 - 7.80 (m, 1H), 7.72 - 7.60 (m, 1H), 4.51 - 4.42 (m, 2H), 2.30 -2.(m, 1H), 1.52- 1.41 (m, 9H), 1.41 - 1.21(m, 2H) ppm.
Step 6: Preparation of(2-(2-(2,2-difluorocyclopropyl)pyrimidin-4-y1)-1,6-naphthyridin-7- yi)methanaminemate To a mixture of tert-butyl ((2-(2-(2,2-d!fluorocyclopropyl)pyrimidin-4-yl)-1,6-naphthyridin-7- yl)methyl)carbamate (90 mg, 0.218 mmol) in DCM (1 mb) was added TEA (770.0 mg, 6.75 mmol, 500 pL) in one portion at 25 °C under N2. The mixture was stirred at 25 ؛־C for 30 min. The mixture was poured into ice-water (20 mb) and extracted with ethyl acetate (20 mb x 1). The organic phase was discarded. To the aqueous phase was added sat.NaHCOs to adjust pH=8. Then the aqueous phase was extracted with ethyl acetate (20 mb x 2). The combined organic phase was washed with brine (10 mb*1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford (2-(2-(2,2-difluorocyclopropyl)pyrimidin- 209 WO 2022/103899 PCT/US2021/058865 4-y5)-1,6-naphthyridin-7-yl)methanamfnemate (70 mg, crude) as Eight yellow solid, which was used directly without purification.
Intermediate 21. [2-[6-(2,2-difiuoro-1 -methyl-cyc topropyl)-2-pyr!dyi]-1,6-naphthyndin-7- yl]methanamine TMSCFs, Na! THF, 70 °C. 1 h Stepl Pd(PPh3)4 hexamethylitin dioxane, 100 °C, 2 h Step 2 Pd(PPh3)2CI2 dioxane, 100 °C, IS h Step 3 Stop 4 Step 1: Preparation of 2-bromo-6-(2,2~d!tiuoro~1-methyl-cyclopropyl)pyr!dine To a mixture of 2-bromo-6-isopropenyl-pyridine (100 mg, 504.90 pmol) and Nai (15.14 mg, 100.98 pmol) in THF (0.8 ml) was added TMSCFS (287.19 mg, 2.02 mmol) dropwise over 30 min at °C under N2. The mixture was stirred at 70 °C for 30 min under N2. The mixture was concentrated under reduced pressure to afford a residue. The residue was purified by silica gel chromatography (PE - PE / EA = 20 /1). The eluent was concentrated under reduced pressure to afford 2-bromo-6-(2,2-difiuoro-1- methyl-cyclopropyl)pyridine (125 mg, 0.504 mmol, 100% yield) as yellow oil. LCMS (ESI) m/z: [M+Hp = 247.9.1H NMR (400 MHz, CDCb) 5 = 7.56 - 7.50 (m, 1H), 7.40-7.37 (m, 1H), 7.30 (d, J = 7.6 Hz, 1H), 2.28 - 2.21 (m, 1H), 1.63 - 1.59 (m, 3H), 1.48 - 1.41 (m, 1H) ppm.
Step 2: Preparation of [6-(2,2-ditiuoro-1-methyicyclopropyl)-2-pyndyl]-tr!methyi-stannane A mixture of 2-bromo-6-(2,2-difluoro-1-methyl-cyclopropyl)pyridine (100 mg, 403.12 pmol), HEXAMETHYLDITIN (264.15 mg, 0.806 mmol, 167 pL) and Pd(PPh3)4 (46.58 mg, 40.31 pmol) in dioxane (2 mL) was stirred at 100 °C for 2 h under N2. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford [6-(2,2-difluoro-1-methylcydopropyl)-2-pyridy0-trimethyl-stannane (2mg, crude) as black brown oil.LCMS (ESI) m/z: [M+Hj+ = 334.0.
Step 3: Preparation of tert-butyl $-[[2-[6-(2,2-difiuoro-1-methyS-cydopropyS)-2-pyridyi]-1l,6- naphthyridm-7-y!]methyi]carbamate A mixture of tert-butyl tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (60 mg, 0.2mmol), [6-(2,2-difluoro-1-methylcydopropy5)-2-pyridyl]-trimethy5-stannane (203.4 mg, 0.613 mmol) and Pd(PPh3)2CI2 (14.34 mg, 20.43 pmol) in dioxane (1 mL) was stirred at 100 °C for 16 h under N2. The mixture was poured into sat. KF (10 mL) and stirred at 20 °C for 30 min. The mixture was extracted with EA (10 mL x 3). The combined organic layers were dried over anhydrous N82SO4, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by silica gel 210 WO 2022/103899 PCT/US2021/058865 chromatography (PE/EA = 10/1 - EA), The eluent was concentrated under reduced pressure to afford tert-butyl A/-[[2-[6-(2,2-d!fluoro-1-methyl-cyclopropyl)-2-pyridylM,6-naphthyridin-7-yl]methy0carbamate (42 mg, 98.49 pmol, 48% yield) as yellow solid.LCMS (ESI) m/z: [M+Hp = 427.0.
Step 4: Preparation of [2-[6~(2,2-d!fluoro-1-methyi-cydopropyi)-2-pyridy0-1,6-naphfhyridin~7- yl]methanamine (intermediate 21) To a solution of tert-butyl /V-[[2-[6-(2,2-d!fluoro-1-methyl-cyclopropyl)-2-pyridylH,6-naphthyridin- 7-yl]methyl]carbamate (42 mg, 98.49 pmol) in DCM (1 mb) was added TFA (462.0 mg, 4.05 mmol, 0.mb) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to afford [2-[6-(2,2-difluoro-1-methyl-cyclopropyl)-2-pyridyl]-1,6-naphthyridin-7-yl]methanamine (43 mg, 97.65 pmol, 99% yield, TFA salt) as yellow solid.LCMS (ESI) m/z: [M+H]+ = 327.0.
Intermediate 22.1-imino-1-oxo-3,5-dihydro-2H-4,1A6-benzoxath!epine-8-carboxyiic acid [bis(ae6toxy)iodo]ben?.8»9(2.1 eq) n- dirhodium tet?־aac6taie(0.1 eq) Step 1 KjCOg MeOH DMSO/H2O,100 °C,4 hrs Pd(OAch, dccD-2HBF4 K2CO3, CO Step2 StepS Step 1: Preparation of M-(8-bromo-1-oxo-3,5-dihydro-2H-4,1A6-benzc)xath!epm-1-yMene)-2,2,2- trifluoro-acetamide A mixture of 8 8-bromo-3,5-dihydro-2H-4,1A4-benzoxathiepine 1 -oxide (50 mg, 191.47 pmol), 2,2,2-trifluoroacetamide (64.93 mg, 574.42 pmol,), [acetoxy(phenyi)-A3-iodanyl] acetate (129.51 mg, 402.09 pmol) and MgO (46.30 mg, 1.15 mmol) in DCM (3 mb) was stirred at 25 CC for 5 min. Then diacetoxyrhodium (8.46 mg, 19.15 pmol) was added to the mixture and the mixture was stirred at 25 °C under N2 for 16 h. The reaction mixture was diluted with MeOH (3 mb) to give A/-(8-bromo-1-oxo-3,5- d!hydro-2H-4 i1A6-benzoxathiepin-1-yl!dene)-2,2,2-trifluoro-acetamide (71 mg, 190.78 pmol, 100% yield) as a yellow liquid which was used for the next step directly. bCMS (ESI) m/z= [M+Hp = 373.2.
Step 2: Preparation of 8-bromo-1-imino-3,5-dihydro-2H-4,1A6-benzoxathiepine 1-oxide A mixture of A(-(8-bromo-1-oxo-3,5-dihydro-2H-4 i1A6-benzoxathiepin-1-ylidene)-2,2,2-trifluoro- acetamide (70 mg, 188.09 pmol) in MeOH (3 mb) was added K2CO3 (181.97 mg, 1.32 mmol) and the mixture was stirred at 25 °C for 4 h. The mixture was diluted with water (10 mb) and filtered to remove the precipitate. The filtrate was separated and the aqueous layer was extracted with DCM (10 mb). The combined organic phase was washed with brine (10 mb), dried over anhydrous N32SO4, filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:EtOAc=20:1-1 :1) to give 8-bromo-1-imino-3,5-dihydro-2H-4,1A6-benzoxathiepine 1-oxide (40 mg, 137.65 pmol, 73% yield) as a white solid.LCMS (ESI) m/z= [M+H]+= 277.2. 211 WO 2022/103899 PCT/US2021/058865 1H NMR (400 MHz, DMSO״d6) 6 = 8.07 (d, J = 2.0 Hz, 1H), 7.817.79־ (m, 1H), 7.46 (d, J= 8.0 Hz, 1H), 4.99 - 4.81 (m, 3H), 4.21 - 4.13 (m, 2H), 3.42 - 3.39 (m, 2H) ppm Step 3: Preparation of 1-imino-1-0x0-3,5-dihydro-2H-4,16-benzoxathiepine-8-carboxylic acidTo a mixture of 8-bromo-1-im!no-3,5-dihydro-2H-4,1A6-benzoxathiepine 1-oxide (40 mg, 144.pmol) and diacetoxypalladium (3.25 mg, 14.48 pmol) in DMSO (3 mL) and H2O (0.3 mL) was added K2CO3 (30.03 mg, 217.27 pmol) and dicyc ؛ohexy3 )؛- dicyclohexylphosphaniumylpropyl)phosphonium;ditetrafluoroborate (17.74 mg, 28.97 pmol). The mixture was degassed and purged with CO for 3 times and then was stirred at 100 °C for 4 h under CO atmosphere (15 psi). The mixture was poured into water (50 mL) and extracted with EA (20.0 mL x2), the combined organics were discarded. The aqueous was adjusted pH to 5 by HCi (1M) and then was extracted with DCM (20.0 mL*3). The combined organic phase was washed with brine (50.0 mL*2), dried over N32SO4, filtered and the filtrate was evaporated to dryness to give 1-imino- 1 -oxo-3,5-dihydro-2H- 4,1A6-benzoxathiepine-8-carboxylic acid (34 mg, crude) as a yellow solid.
Example 2. M-[[2-[6-(azetidin-1 -yl)-2-pyridyi]-1,6-naphthy ridin-7-yl]methyl]-1,1 -dioxo-3,5-dihydro- 2H-4,1A6-benzoxathiepine-8-carboxamlde stannane ־ methyl ؛ tr [״ dm-1-yl)-2-pyridyl ؛ azet ־) 6 ] Step 1. Preparation of To a solution of 2-(azetidin-1-yl)6 ־-bromo ־pyridine (150 mg, 703.98 pmol) in dioxane (3 mL) was added HEXAMETHYLDITIN (461.28 mg, 1.41 mmol) and Pd(PPh3)4 (81.35 mg, 70.40 pmol). The mixture was purged with N2 3x and then was stirred at 100 CC for 2 h under N2 atmosphere. The reaction mixture was diluted with H2O (200 mL) and extracted with EA (150 mL x 3). The combined organic layers were washed with brine (200 mL), dried over N82SO4, filtered and the filtrate was concentrated under reduced pressure to give [6-(azetidin-1-yl)-2-pyridyi]-trimethyl-stannane (209 mg, crude) as brown oil which was used into the next step without further purification. LCMS (ESI) m/z: [M+H]* = 299.3.
Step 2. Preparation of tert-butyl M-[[2-[6-(azetidin-1-yll)-2-pyridyn-1,6-naph thyridin-7- yljmethyljcarbamate To a solution of tert-butyl A/-[(2-chloro-1,6-naphthyridin-7-yl)methyl]carbamate (100 mg, 340.pmol) in dioxane (2 mL) was added [6-(azetidin-1-yl)-2-pyridyl]-trimethyl-stannane (202.2 mg, 680.7 pmol pmol) and Pd(PPh3)2Ck (23.9 mg, 34.04 pmol). The mixture was purged with N2 for 3 times and then was stirred at 100 °C for 12 h under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried 212 WO 2022/103899 PCT/US2021/058865 over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SIO2, Petroleum ether/Ethyl acetate=10:1 - 1:1) to give tert- butyl /V-((2-(6-(azetidin-1-yl)pyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (70 mg, 173.45 pmol, 51% yield) as a yellow solid. LCMS (ESI) m/z: [M+Hp = 392.4. 1H NMR (400 MHz, CDCb) 6 = 9.22 (s, 1H), 8.68 (d,= 8.8 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.98 (d, 7.2 Hz, 1H), 7.93 (s, 1H), 7.72-7.61(m, 1H), 6.43 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 4.8 Hz, 2H), 4.18 - 4.14 (m, 4H), 2.18 (s, 2H), 1.50 (s, 9H) ppm.
Step 3. Preparation of [2-[6-(azetidin-1-yl)-2-pyridy0-1,6-naphthyr!din-7-y0 methanamine To a solution of tert-butyl A/-((2-(6-(azetidin-1-yl)pyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)carbamate (70 mg, 178.82 pmol) in DCM (3 mL) was added TFA (1 mb) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into saturated aqueous NaHCO3 (30 mb) and extracted with EA (30 mb x 3). The combined organic layers were washed with brine (30 mb), dried over Na2S04, filtered and the filtrate was concentrated under reduced pressure to give [2-[6-(azetidin-1- yi)-2-pyridy0-1,6-naphthyridin-7-yl] methanamine (60 mg, crude) as a yellow solid, which was used into the next step without further purification. LCMS (ESI) m/z: [M+HF = 292.4.
Step 4. Preparation of M-[[2-[6-(azetidin-1-yi)-2-pyridyl] -1,6-naphthyridin-7-yHmethyi]-1,1-dioxo- 3,5-dihydro-2H-4,1 G-benzoxathiepine-B-carboxamide (1) To a solution of 1,1-dioxo-3,5-dihydro-2H-4,1 16-benzoxathiepine-8-carboxylic acid (24.94 mg, 102.97 pmol) in DCM (1 mb) was added EDCI (21.38 mg, 111.55 pmol), HOBt (15.07 mg, 111.55 pmol) and DIEA (33.27 mg, 257.42 pmol). And then [2-[6-(azetidin-1-yl)-2-pyridyl]-1,6-naphthyridin-7-yl] methanamine (25 mg, 85.81 pmol) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (20 mb) and extracted with EA (30 mb * 3). The combined organic layers were washed with brine (30 mb), dried over N32SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-TLC (SiO2, DCM:MeOH = 15:1) to give the crude product. Then the crude product was further purified by Prep-HPbC (0.1% FA additive). The eluent was concentrated under reduced pressure to remove MeCN and the residue was lyophilized to give A/-[[2-[6-(azetid!n-1-yl)-2-pyridylH i6-naphthyridin-7-yl]methyl]-1,1-dioxo-3,5-dihydro-2H-4,16- benzoxathiepine-8-carboxamide (10.21 mg, 19.21 pmol, 22% yield) as a yellow solid. LCMS (ESI) m/z= [M+HF = 261.9.1H NMR (400 MHz, CD3OD) 6= 9.33 (s, 1H), 8.69 - 8.63 (m, 2H), 8.62 - 8.57 (m, 1H), 8.39 (s, 1H), 8.(d, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.73 - 7.65 (m, 2H), 6.54 (d, J= 7.6 Hz, 1H), 5.07 (s, 2H), 4.95 (s, 2H), 4.39 - 4.34 (m, 2H), 4.17 - 4.15 (m, 4H), 3.58 - 3.53 (m, 2H), 2.53 - 2.40 (m, 2H) ppm.
The following examples in Table 2 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 2. 213 WO 2022/103899 PCT/US2021/058865 Table 2. Compounds of the Invention # LCMS (m/z) 1H NMR 304 516.1 1H NMR (400 MHz, CD:OD) 6= 9.33 (s, 1H), 8.69 - 8.63 (m, 2H), 8.62 - 8.57 (m, 1H), 8.39 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.73 - 7.65 (m, 2H), 6.54 (d, J = 7.6 Hz, 1H), 5.07 (s, 2H), 4.95 (s, 2H), 4.39 - 4.34 (m, 2H), 4.17 - 4.15 (m, 4H), 3.58 - 3.53 (m, 2H), 2.53 - 2.40 (m, 2H) ppm. 303 504.2 1H NMR (400 MHz, CD3OD) 5= 9.30 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 1.Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.96 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.73 - 7.61 (m, 2H), 6.78 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 4.38 - 4.29 (m, 2H), 3.57 - 3.49(m, 2H), 3.19 (s, 6H) ppm. 155 588.2 ؛H NMR (400 MHz, CDCb) 6 = 9.28 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.55 (d, J = 1.Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.21 - 8.19 (m, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.84 - 7.77 (m, 1H), 7.72 - 7.70 (m, 1H), 7.49 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 5.2 Hz, 4H), 4.40 (d, J = 12.8 Hz, 1H), 4.24 - 4.20 (m, 2H), 4.13 - 4.(m, 1H), 3.80 - 3.79 (m, 2H), 3.40 - 3.28 (m, 1H), 2.67 - 2.61 (m, 2H), 1.35 - 1.32 (m, 9H) ppm. 159 588.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.66 - 9.59 (m, 1H), 9.40 (s, 1H), 8.71 - 8.60 (m, 2H), 8.53 (d, J = 2.0 Hz, 1H), 8.28 - 8.26 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.76 - 7.72 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 4.82 (d, J = 5.2 Hz, 2H), 4.38 - 4.24 (m, 3H), 4.04 - 3.99 (m, 1H), 3.74 - 3.60 (m, 3H), 2.52 - 2.52 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H), 1.19 -1.14 (m, 3H) ppm. 282 574.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65-9.63 (m, 1H), 9.41 (s, 1H), 8.66 - 8.64 (m, 2H), 8.55 (d, J = 2.0 Hz, 1H), 8.28-8.26 (m , 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.75 - 7.72 (m , 2H), 7.03 (d, J = 8.8 Hz, 1H), 4.99 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.32 (br d, J = 11.6 Hz, 2H), 4.25 - 4.22 (m, 2H), 3.70 - 3.65 (m, 4H), 2.53 (br d, J = 1.6 Hz, 2H), 1.22 (d, J = 6.0 Hz, 6H) ppm 190 516.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.59 (m, 1H), 9.36 (s, 1H), 8.68 - 8.58 (m, 2H), 8.56 - 8.51 (m, 1H), 8.27 - 8.25 (m, 1H), 7.80 - 7.71 (m, 3H), 7.42 (d, J = 7.2 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.32 - 4.18 (m, 2H), 3.71 - 3.66 (m, 2H), 3.53 - 3.49 (m, 2H), 3.07 - 2.95 (m, 5H) ppm. 176 516.2 1H NMR (400 MHz, CD:OD) 6 = 9.19 (s, 1H), 8.62 (d, J= 1.6 Hz, 1H), 8.45 (d, J = 4.0 Hz, 2H), 8.27 -8.17 (m, 2H), 7.86 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H), 4.89 (br s, 2H), 4.36 - 4.32 (m, 2H), 3.61 - 3.51 (m, 4H), 3.20 - 3.11 (m, 2H), 2.89 (s, 3H) ppm. 167 541.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.43 (s, 1H), 8.76 - 8.70 (m, 1H), 8.69 - 8.61 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.32 - 8.23 (m, 2H), 8.02 - 7.94 (m, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.12-7.16 (m, 1H), 6.65-6.33 (m, 1H), 4.98 (s, 2H), 4.88 - 4.67 (m, 4H), 4.24 - 4.21 (m, 2H), 3.76 - 3.62 (m, 2H) ppm. 214 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 165 519.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.74 - 9.58 (m, 1H), 9.42 (s, 1H), 8.71 (d, J = 8.Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.30 -8.23 (m, 1H), 8.(d, J = 7.6 Hz, 1H), 7.92 - 7.8 5 (m, 1H), 7.83 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 6.(d, J = 8.4 Hz, 1H), 5.56 - 5.43 (m, 1H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.29 - 4.18 (m, 2H), 3.76 - 3.63 (m, 2H), 1.39 (d, J = 6.0 Hz, 6H) ppm 240 592.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.70 (t, J = 5.6 Hz, 1H), 9.39 (s, 1H), 8.68 - 8.(m, 2H), 8.46-8.40 (m, 1H), 8.18-8.16 (m, 1H), 7.91 (d,J-7.6 Hz, 1H), 7.83 (s, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.03 (d, J= 8.8 Hz, 1H), 5.02 (s, 2H), 4.82-4.81 (m, 2H), 4.32 - 4.21 (m, 4H), 3.77 - 3.75 (m, 2H), 3.69 - 3.67 (m, 2H), 2.47 (br s, 2H), 1.21 (d, J = 6.4 Hz, 6H) ppm. 143 608.1 ؛H NMR (400 MHz, DMSO-de) 6= 9.75-9.68 (m, 1H), 9.40 (s, 1H), 8.68-8.61 (m, 2H), 8.51 (d, J= 1.6 Hz, 1H),8.49 (s, 1H), 8.41 (d, J= 1.6 Hz, 1H), 7.92 - 7.84 (m, 2H), 7.77 - 7.73 (m. 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.20 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.32 - 4.22 (m, 4H), 3.81 - 3.70 (m, 2H), 3.68 - 3.61 (m, 2H), 2.54 - 2.52 (m, 2H), 1.21 (d, 5.6 Hz, 6H) ppm. 284 522.2 1H NMR (400 MHz, DMSO-de) 0= 9.73 - 9.69 (m, 1H), 9.39 (s, 1H), 8.65 (s, 2H), 8.41 (d, J= 1.2 Hz, 1H), 8.22-8.14 (m, 1H), 7.84-7.81 (m, 2H), 7.72 -7.68 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.02 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.78 - 3.75 (m, 2H), 3.15 (s, 6H) ppm 212 588.3 1H NMR (400 MHz, DMSO-de) 6 = 9.64 (s, 1H), 9.39 (s, 1H), 8.67 - 8.59 (m, 2H), 8.55 (d, J = 2.0 Hz, 1H), 8.28 - 8.26 (m, 1H), 7.82 - 7.72 (m, 3H), 6.90 - 6.84 (m, 1H), 4.99 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.35 - 4.26 (m, 2H), 4.26 - 4.21 (m, 2H), 3.71 - 3.63 (m, 4H), 2.52 - 2.47 (m, 2H), 2.34 (s, 3H), 1.21 (d, J = 6.0 Hz, 6H) ppm. 175 574.0 1H NMR (400 MHz, MeOD) 6 = 9.34 - 9.30 (m, 1H), 8.69 - 8.64 (m, 1H), 8.63 - 8.(m, 2H), 8.54- 8.50 (m, 1H), 8.23-8.18 (m, 1H), 7.98- 7.95 (m, 1H), 7.95-7.91 (m, 1H), 7.78 - 7.72 (m, 1H), 7.62 - 7.58 (m, 1H), 7.00 - 6.95 (m, 1H), 4.95- 4.93 (m, 2H), 4.86 - 4.84 (m, 2H), 4.37 - 4.29 (m, 2H), 4.16 - 3.98 (m, 2H), 3.85 - 3.74 (m, 2H), 3.62 - 3.50 (m, 2H), 2.64 -2.52 (m, 2H), 1.31 - 1.29 (m, 6H) ppm 210 515.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m , 1H), 9.41 (s, 1H), 8.73 - 8.68 (m, 1H), 8.63 - 8.61 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.46 (br s, 1H), 8.35 (d, J = 7.2 Hz,1H), 8.30 - 8.26 (m, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 7.6 Hz,1H), 7.51 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.83 (d, J = 6.0 Hz, 2H), 4.24 - 4.21 (m,2H), 3.69 - 3.67 (m, 2H), 1.57 (s, 3H), 1.35 - 1.33 (m, 2H), 0.92 - 0.90 (m, 2H) ppm 208 551.2 1H NMR (400 MHz, DMSO-de) 6 = 9.69 - 9.58 (m, 1H), 9.46 - 9.41 (m, 1H), 8.75 - 8.66 (m, 2H), 8.58 - 8.52 (m, 1H), 8.48 -8.46 (m, 1H), 8.31 - 8.24 (m, 1H), 8.04 - 7.(m, 1H), 7.90 - 7.82 (m, 1H), 7.78 - 7.71 (m, 1H), 7.67 - 7.54 (m, 1H), 6.79 - 6.47(m, 1H), 5.03 - 4.96 (m, 2H), 4.86 - 4.80 (m, 2H), 4.28 - 4.20 (m, 2H), 3.72 - 3.65 (m, 2H), 1.51-1.43 (m, 2H), 1.38 - 1.31 (m, 2H) ppm. 19F NMR (400 MHz, DMSO-de) 6 = - 118.667 ppm. 215 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 204 502.1 1H NMR (4Q0 MHz, DMSO-ds) 6 = 9.84 - 9.81 (m, 1H), 9.42 (s, 1H), 9.29 (d, J = 2.Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.72 - 8.66 (m, 1H), 8.64 - 8.6Q (m, 1H), 8.34 (d, J = 7.6 Hz, 1H), 7.90 - 7.82 (m, 2H), 7.47 (d, J= 7.6 Hz, 1H), 5.07 (s, 2H), 4.85 (d, J= 5.6 Hz, 2H), 4.35 - 4.23 (m, 2H), 3.90 - 3.82 (m, 2H), 2.28 - 2.19 (m, 1H), 1.15 -1.(m, 4H) ppm. 285 527.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.66 - 9.63 (m, 1H), 9.44 (s, 1H), 8.77 - 8.75 (m, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.46 (d, J = 7.6 Hz, 1H), 7.(s, 3H), 7.85 (s, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.27 (d, J= 8.0 Hz, 1H), 4.98 (s,2H), 4.83 (d, J = 6.0 Hz, 2H), 4.24 - 4.22 (m, 2H), 3.69 - 3.67 (m, 2H) ppm. 291 510.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.69 - 9.56 (m, 1H), 9.39 (s, 1H), 8.66 (s, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.43 (s, 1H), 8.31 - 8.22 (m, 1H), 7.88 - 7.79 (m, 2H), 7.77 - 7.62 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.29 - 4.16 (m, 2H), 3.75 - 3.61 (m, 2H) ppm. 276 558.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.64 (brt, J = 5.6 Hz, 1H), 9.39 (s, 1H), 8.70 - 8.67 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.81 - 7.73 (m, 3H), 6.82 (d, J = 8.8 Hz, 1H), 4.98 (s, 2H), 4.82 - 4.76 (m,4H), 4.24 - 4.21 (m, 2H), 3.88 (br d, J = 12.0 Hz, 2H), 3.70 - 3.67 (m, 4H), 3.19 - 3.14 (m, 1H), 1.94 (d, J = 8.4 Hz, 1H) ppm. 274 490.1 1H NMR (400 MHz, DMSO-de) 6 = 9.64 - 9.61 (m, 1H), 9.37 (s, 1H), 8.65 (s, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.27-8.25 (m, 1H), 7.79 (s, 1H), 7.76-7.73 (m, 2H), 7.58 - 7.54 (m, 1H), 6.75 - 6.73 (m, 1H), 6.62 (d, J =8 .0 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.24-4.22 (m, 2H), 3.69 - 3.67 (m, 2H), 2.92 (d, J = 4.8 Hz, 3H) ppm 264 501.2 1H NMR (400 MHz, DMSO-de) 6 = 9.65-9.62 (m, 1H), 9.41 (s, 1H), 8.69 - 8.67 (m,1H), 8.62 - 8.60 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.48 (br d,Jj= 3.2 Hz, 1H), 8.34 (d, J = 7.2 Hz, 1H), 8.27-8.25 (m, 1H), 7.86 - 7.82 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.(d, J = 7.2 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.69 - 3.67 (m, 2H), 2.26 - 2.20 (m, 1H), 1.12 -1.04 (m, 4H) ppm. 289 503.3 1H NMR (400 MHz, DMSO-d6) 6= 9.65 (s, 1H), 9.42 (s, 1H), 8.76 - 8.68 (m, 2H), 8.47 (d, J= 1.2 Hz, 1H), 8.43 - 8.41 (m, 1H), 8.27 (d, J= 1.6 Hz, 1H), 7.92 - 7.84(m, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 4.98 (s, 2H), 4.(d, J = 5.6 Hz, 2H), 4.27 -4.19 (m, 2H), 3.75 - 3.64 (m, 2H), 3.22 - 3.12 (m, 1H), 1.(d, J = 6.8 Hz, 6H) ppm. 281 525.2 1H NMR (400 MHz, CD3OD) 5 = 9.35 (s, 1H), 8.77 - 8.73 (m, 2H), 8.66 - 8.62 (m, 2H), 8.23-8.21 (m, 1H), 8.14-8.10 (m, 1H), 8.00 (s, 1H), 7.84-7.82 (m, 1H), 7.(d, J = 7.6 Hz, 1H), 5.05 (s, 2H), 4.94 (s, 2H), 4.35 - 4.33 (m, 2H), 3.54 - 3.52 (m, 2H), 2.18 - 2.08 (m, 3H) ppm 216 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 280 521.2 1H NMR (400 MHz, CD:OD) 6 = 9.44 (s, 1H), 8.82 (d, J= 8.8 Hz, 1H), 8.69 (d,J= 8.8 Hz, 1H), 8.65- 8.56 (m, 2H), 8.23-8.21 (m, 1H), 8.10 (s, 1H), 8.04-8.00 (m, 1H), 7.74 - 7.72 (m, 1H), 7.65 (d, J = 7.6 Hz, 1H), 5.05 (s, 2H), 4.97 (s, 2H), 4.35 - 4.33 (m, 2H), 3.54 - 3.52 (m, 2H), 1.83 - 1.77 (m, 6H) ppm 241 517.2 1H NMR (400 MHz, DMSO) 6 = 9.36 - 9.30 (m, 1H), 8.73 (d, J = 8.8 Hz, 1H), 8.66 - 8.59 (m, 2H), 8.53 - 8.45 (m, 1H), 8.28 - 8.20 (m, 2H), 7.98 (s, 1H), 7.92 - 7.84 (m, 1H), 7.65 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.06 - 5.04 (m, 2H), 4.94 (s, 2H), 4.45 - 4.38 (m, 1H), 4.37 - 4.32 (m, 2H), 3.56 - 3.50 (m, 2H), 0.92 - 0.76 (m, 4H) ppm. 239 505.2 ؛H NMR (400 MHz, CD3OD) 5 = 9.32 (s, 1H), 8.71 - 8.67 (m, 1H), 8.64 - 8.59 (m, 2H), 8.26-8.18 (m, 2H), 7.97 (s, 1H), 7.85-7.81 (m, 1H), 7.65 (d, J=7.6 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 4.58 - 4.52 (m, 2H), 4.37 - 4.(m, 2H), 3.57 - 3.51 (m, 2H), 1.48 - 1.45 (m, 3H) ppm. 237 545.1 1H NMR (400 MHz, DMSO-de) 0 = 9.67 - 9.65 (m, 1H), 9.46 (s, 1H), 8.78 (d, J= 8.Hz, 1H), 8.61 (d, J = 7.6 Hz, 1H), 8.54 (d, 2.0 Hz, 1H), 8.50 (d, J= 8.8 Hz, 1H),8.29-8.21 (m, 2H), 7.87 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 4.98 (s, 2H), 4.84 (d, J = 5.6 Hz, 2H), 4.27 - 4.20 (m, 2H), 3.71 - 3.65 (m, 2H) ppm. 183 543.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.62 (m, 1H), 9.43 (s, 1H), 8.76 - 8.70 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.28 - 8.25 (m, 1H), 8.01 - 7.97 (m, 1H), 7.85 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 6.98 (s, 1H), 4.98 (s, 2H), 4.(d, J = 5.6 Hz, 2H), 4.35 - 4.32 (m, 2H), 4.24 - 4.22 (m, 2H), 3.90 - 3.87 (m, 2H), 3.- 3.67 (m, 2H), 2.73 - 2.68 (m, 2H) ppm. 169 566.2 1H NMR (400 MHz, DMSO-d6) 6= 9.66 (s, 1H), 9.47 (s, 1H), 8.90 (d, 8.4 Hz, 1H),8.78 (d, J = 8.8 Hz, 1H), 8.66 (d, J = 7.6 Hz, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.37 ( s, 1H), 8.31 - 8.21 (m, 2H), 8.20 - 8.12 (m, 1H), 7.91 (s, 2H), 7.88 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 4.99 (s, 2H), 4.85 (d, J = 5.6 Hz, 2H), 4.28 -4.19 (m, 2H), 3.71 - 3.(m, 2H), 2.57 (s, 6H) ppm. 213 566.2 1H NMR (400 MHz, DMSO-ds) 6 = 9.67 (t, J = 6.0 Hz, 1H), 9.39 (s, 1H), 8.65 - 8.(m, 3H), 8.30-9.29 (m, 1H),7.94 - 7.89 (m, 2H), 7.81 (s, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 (br d, J = 11.2Hz, 2H), 3.70 - 3.65 (m, 2H), 3.43 (s, 3H), 2.47 (br s, 2H), 1.21 (d, J = 6.4 Hz, 6H) ppm. 206 582.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.75 - 9.74 (m, 1H), 9.40 (s, 1H), 8.68 - 8.61 (m, 3H), 8.47 (d, 8.0 Hz, 1H), 8.11 (d, 8.4 Hz, 1H), 7.91 (d,J=7.6 Hz, 1H), 7.84(s, 1H), 7.84 - 7.56 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.84 (d, J = 5.6 Hz, 2H), 4.(d, J= 12.4 Hz, 2H), 3.68 - 3.65 (m, 2H), 3.39 (s, 3H), 2.46 (s, 2H), 1.21 (d, J = 6.Hz, 6H) ppm. 217 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 195 546.2 1H NMR (400 MHz, DMSO-ds) 6 = 9.54 (d, J = 6.0 Hz, 1H), 9.40 (s, 1H), 8.73 - 8.(m, 2H), 8.51 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H), 8.22 - 8.20 (m, 1H), 7.91 (d, J = 7.Hz, 1H), 7.81 (s, 1H), 7.78 - 7.72 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.Hz, 1H), 4.82 (d, J = 6.0 Hz, 2H), 4.32 (d, J = 12.0 Hz, 2H), 3.73 - 3.64 (m, 2H), 3.(s, 3H), 2.73 (s, 3H), 2.54 - 2.53 (m, 2H), 1.22 (d, J = 6.0 Hz, 6H) ppm. 192 576.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.60 - 9.56 (m, 1H), 9.40 (s, 1H), 8.70 - 8.60 (m, 2H), 8.53 (d, J = 2.0 Hz, 1H), 8.33 - 8.30 (m, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.76 - 7.72 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.90 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 (br d, J = 11.2 Hz, 2H), 3.73 - 3.63 (m, 2H), 3.43 (s, 3H), 3.31 - 3.31 (m, 3H), 2.53 (br d, J = 2.0 Hz, 2H), 1.21 (d, J = 6.0 Hz, 6H) ppm. 180 567.2 ؛H NMR (400 MHz, DMSO-d6) 6 = 9.70 - 9.66 (m, 1H), 9.48 (d, J = 0.4 Hz, 1H), 8.- 8.73 (m, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.63 - 8.57 (m, 2H), 8.32 - 8.29 (m, 1H), 7.(d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.71 (d, J = 4.8 Hz, 1H), 4.83 (d, J = 6.0 Hz, 2H), 4.68 (br d, J = 12.4 Hz, 2H), 3.65 - 3.43 (m, 2H), 3.43 (s, 3H), 2.63 (br d, J = 2.4 Hz, 2H), 1.20 (d, J = 6.0 Hz, 6H) ppm. 157 583.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.75-9.71 (m, 1H), 9.49 (s, 1H), 8.80 - 8.75 (m, 1H), 8.68 (d, J= 8.8 Hz, 1H), 8.61 (d, J= 4.8 Hz, 2H), 8.48 - 8.45 (m, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.93 - 7.55 (m, 3H), 4.86 (d, J = 6.0 Hz, 2H), 4.69 (d, J = 12.8 Hz, 2H), 3.67 - 3.60 (m, 2H), 3.40 (s, 3H), 2.68 - 2.60 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H) ppm. 27Q 537.3 1H NMR (400 MHz, MeOD) 6 = 9.34 (s, 1H), 8.75 - 8.71 (m, 1H), 8.66 - 8.61 (m, 2H), 8.55 - 8.50 (m, 1H), 8.24 - 8.21 (m, 1H), 7.99 (s, 1H), 7.96 - 7.91 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 5.05 (s, 2H), 4.94 (s, 2H), 4.37 - 4.33 (m, 2H), 3.55-3.52 (m, 2H), 3.21 -3.14 (m, 1H), 2.49 - 2.42 (m, 1H), 2.00 - 1.90 (m, 1H) ppm. Chiral SFC: AD-3-IPA+ACN(DEA)-40-3ML-35T, Ri = 1.639 min, ee %= 10Q.0 %. 267 537.3 1H NMR (400 MHz, MeOD) 6 = 9.34 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.65 - 8.60 (m, 2H), 8.54-8.51 (m, 1H), 8.24 - 8.21 (m, 1H), 7.99 (s, 1H), 7.96 - 7.91 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 5.05 (s, 2H), 4.94 (s, 2H), 4.38 - 4.31 (m, 2H), 3.56-3.51 (m, 2H), 3.21 - 3.12 (m, 1H), 2.52 - 2.41 (m, 1H), 2.02 -1.91 (m, 1H) ppm.Chirai SFC: AD-3-؛PA+ACN(DEA)-403־ML35־T, Ri = 2.008 min, ee %= 98.252 %. 217 538.3 1H NMR (400 MHz, MeOD) 6 = 9.45 - 9.40 (m, 1H), 8.99 - 8.90 (m, 1H), 8.81 - 8.(m, 2H), 8.66 - 8.63 (m, 1H), 8.56 - 8.49 (m, 1H), 8.27 - 8.21 (m, 1H), 8.06 - 8.01 (m, 1H), 7.70 - 7.63 (m, 1H), 5.10 - 5.06 (m, 2H), 4.97 (s, 2H), 4.40 - 4.33(m, 2H), 3.58 - 3.52 (m, 2H), 3.30 - 3.25 (m, 1H), 2.64 - 2.52 (m, 1H), 2.15 - 2.00 (m, 1H) ppm.SFC: OD-3-MeOH(DEA)-40-3ML-35T.lcm, rt = 1.629, ee%=100%. 218 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 218 538.3 1H NMR (4Q0 MHz, MeOD) 6 = 9.45 - 9.38 (m, 1H), 8.97 - 8.92 (m, 1H), 8.80 - 8.(m, 2H), 8.66 - 8.62 (m, 1H), 8.54 - 8.50 (m, 1H), 8.46 - 8.40 (m, 1H), 8.26 - 8.21 (m, 1H), 8.06 - 8.02 (m, 1H), 7.69 - 7.64 (m, 1H), 5.09 - 5.06 (m, 2H), 4.99 - 4.95 (m, 2H), 4.40 - 4.34 (m, 2H), 3.58 - 3.52 (m, 2H), 3.31 - 3.25 (m, 1H), 2.64 - 2.53 (m, 1H), 2.14 - 2.01 (m, 1H) ppm.SFC: OD-3-MeOH(DEA)-40-3ML-35T.lcm, rt = 2.531, ee%=1 00%. 219 551.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.68 - 9.65 (m, 1H), 9.44 (s, 1H), 8.76 - 8.67 (m, 2H), 8.56 - 8.50 (m, 2H), 8.28 - 8.25 (m, 1H), 8.05-8.00 (m, 1H), 7.85 (s, 1H), 7.76- 7.70 (m, 2H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.26 - 4.20 (m, 2H), 3.71 - 3.(m, 2H), 2.65 - 2.58 (m, 1H), 1.81 -1.73 (m, 1H), 1.69 (s, 3H) ppm.Chiral SFC: OJ-3-MeOH(DEA)-40-3ML-35T, Rt= 0.987 min, ee % = 100 %. 214 551.1 ؛H NMR (400 MHz, DMSO-d6) 5 = 9.66 - 9.63 (m, 1H), 9.44 (s, 1H), 8.76 - 8.67 (m, 2H), 8.59 - 8.48 (m, 2H), 8.28 - 8.25 (m, 1H), 8.05 - 8.00 (m, 1H), 7.85 (s, 1H), 7.75 - 7.69 (m, 2H), 4.98 (s, 2H), 4.83 (d, J = 6.0 Hz, 2H), 4.29 - 4.18 (m, 2H), 3.73 - 3.(m, 2H), 2.64 - 2.60 (m, 1H), 1.81-1.72 (m, 1H), 1.69 (s, 3H) ppm.Chiral SFC: OJ-3-MeOH(DEA)-40-3ML-35T, Rt= 1.176 min, ee % = 100 %. 37 592.5 ؛H NMR (400 MHz, DMSO-d6) 6 = 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.(m, 1H), 9.44 (s, 1H), 8.76 - 8.67 (m, 2H), 8.59 - 8.48 (m, 2H), 8.28 - 8.25 (m, 1H), 8.05 - 8.00 (m, 1H), 7.85 (s, 1H), 7.75 - 7.69 (m, 2H), 4.98 (s, 2H), 4.83 (d, J = 6.Hz, 2H), 4.29 - 4.18 (m, 2H), 3.73 - 3.64 (m, 2H), 2.64 - 2.60 (m, 1H), 1.81 -1.72 (m, 1H), 1.69 (s, 3H) ppm. 588.5 1H NMR (400 MHz, DMSO-d6) 0 = 9.56-9.53 (m, 1H), 9.39 (s, 1H), 8.65 - 8.59 (m, 2H), 8.48 (s, 1H),8.28-8.25 (m, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.80- 7.75 (m, 2H), 7.(d, J = 8.4 Hz,1H), 7.01 (s, 1H), 4.88 (d, J = 5.6 Hz, 2H), 4.41 - 4.28 (m, 4H), 3.69 - 3.64 (m, 3H), 2.54 - 2.52 (m, 2H), 2.32 - 2.30 (m, 1H), 2.20-2.16 (m, 1H), 1.34 (d, J=7.2 Hz, 3H ), 1.21 (d, J = 6.4Hz, 6H) ppm. 13 606.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.70 (m, 1H), 9.40 (s, 1H), 8.65 (m, 2H), 8.40 (m, 1H), 8.20 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.78 - 7.70 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.12 - 5.03 (m, 1H), 5.01 - 4.91 (m, 1H), 4.82 (m, 2H), 4.36 - 4.(m, 3H), 4.03 (m, 1H), 3.77 - 3.63 (m, 3H), 2.53 - 2.52 (m, 2H), 1.24-1.16 (m, 9H) ppm. 101 588.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.51 (m, 1H), 9.40 (s, 1H), 8.70 - 8.59 (m, 2H), 8.40 (s, 1H), 8.16 (s, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.80 (s, 1H), 7.74 (m, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.06 (s, 2H), 4.81 (brd, J =5.6 Hz, 2H), 4.34 - 4.27 (m, 2H), 4.25 - 4.17 (m, 2H), 3.73 - 3.62 (m, 4H), 2.53 - 2.52 (m, 2H), 2.48 - 2.47 (m, 3H), 1.21 (d, J =6.3 Hz, 6H) ppm. 219 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 63 519.1 1H NMR (4Q0 MHz, DMSO-d6) 6 = 9.72-9.69 (m, 1H), 9.41 (s, 1H), 8.71 - 8.66 (m, 1H), 8.64 - 8.58 (m, 1H), 8.41 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.18 - 8.16 (m, 1H), 7.88 - 7.81 (m, 2H), 7.46 (d, J = 7.6 Hz, 1H), 5.03 (s, 2H), 4.83 (d, J =5.6 Hz, 2H), 4.28 - 4.19 (m, 2H), 3.80 - 3.72 (m, 2H), 2.28 - 2.18 (m, 1H), 1.16-1.00 (m, 4H) ppm.
Example 3. /V-[[2-[6-(azetid!n-1 -yl)~2-pyridyl]-1,6-naphthy ridm-7-ynmethy!]-1,1 -d؛oxo ״ 3,5 ״ d؛hydro~ 2H-4,1A6-benzoxathiepme-8-carbaxamide Step 1. Preparation of(6-fluoro-2-pyridyl)-trimethyl-stannaneTo a mixture of 2-bromo-6-fluoro-pyridine (500 mg, 2.84 mmol) in dioxane (5 mL) was added trimethyl(trimethylstannyl)stannane (2.79 g, 8.52 mmol) and Pd(PPh3)4 (328.31 mg, 284.11 pmol). The mixture was purged with N2 for 1 min and then was stirred at 100 °C for 2 h. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum to give (6-fluoro-2-pyridyl)-trimethyl-stannane (730 mg, crude) as brown oil. LCMS (ESI) m/z= [M+HP= 261.9.
Step 2. Preparation oftert-butyl AH[2-(6-fluoro-2-pyridyl)-1,6-naphthyr!din-7-yi]methy!]carbamate To a mixture of tert-butyl /V-[(2-chloro-1,6-naphthyridin-7-yl)methy0carbamate (300 mg, 1.mmol) and (6-fluoro-2-pyridyl)-trimethyl-stannane (530.85 mg, 2.04 mmol) in dioxane (6 mL) was added Pd(PPh3)2CI2 (71.68 mg, 102.13 pmol) and the mixture was purged with N2 for 1 min. The resulting mixture was stirred at 110 °C for 16 h. Then the reaction mixture was poured into Sat. KF (30 mL) and was stirred for 30 min and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The reaction mixture was purified by column chromatography (SiO2, PE:EtOAc=20:1-1:1) to give tert-butyl A/-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methyl]carbamate (230 mg, 649.03 pmol, 64% yield) as a yellow solid.LCMS (ESI) m/z: [M+HF = 355.1.1H NMR (400 MHz, CDCb) 6 = 9.26 (s, 1H), 8.63 - 8.58 (m, 2H), 8.41-8.39 (m, 1H), 8.04-7.98 (m, 1H), 7.94 (s, 1H), 7.09 - 7.06 (m, 1H), 5.49 (br s, 1H), 4.69 (br d, J = 5.2 Hz, 2H), 1.50 (s, 9H) ppm. 220 WO 2022/103899 PCT/US2021/058865 Step 3. Preparation of [2-(6-fiuoro-2-pyr!dyi)-1,6-naphthyndiri-7-yi]methariamine A mixture offert-butyl A/-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyrid!n-7-yl]methyl]carbamate (220 mg, 620.81 pmol) in HCI/dioxane (2 mL) was stirred at 25 °C for 1 hr. The mixture was evaporated to dryness and the residue was triturated with MTBE (20 mL x 2). The mixture was filtered and the filter cake was evaporated to dryness to give [2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methanamine (180 mg, crude, HCI) as a yellow solid.LCMS (ESI) m/z: [M+H]* = 255.1.
Step 4. Preparation of Af-[[2-(6-fluoro-2-pyndyl)-1,6-naphthyrid!n-7-yl]methy0-1,1-dioxo-3,5- dihydro-2H-4,1A6-benzoxathiepine-8-carboxamide To a mixture of [2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-yl]methanamine (180 mg, 619.15 pmol) and 1,1-dioxo-3,5-dihydro-2H-4,1A6- benzoxathiepine-8-carboxylic acid (180 mg, 0.743 mmol) in DCM (mL) was added DIEA (320.08 mg, 2.48 mmol), EDCI (178 mg, 0.928 mmol) and HOBt (125.49 mg, 928.72 pmol). The mixture was stirred at 25 °C for 1 hr. The mixture was poured into water (20 mL) and extracted with EA (10.0 mL x 3). The combined organics were washed with brine (20.0 mL), dried over Na2SO4, filtered and the filtrate was evaporated to dryness. The residue was purified by prep-HPLC (0.1% FA condition) and the eluent was concentrated under vacuum to remove the MeCN. The residue was lyophilized to give A/-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-y0methyl]-1,1-dioxo-3,5-dihydro-2H- 4,1A6-benzoxathiepine-8-carboxamide (253 mg, 0.528 mmol, 85% yield) as a white solid. LCMS (ESI) m/z: [M+Hp = 479.0.1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.61 (m, 1H), 9.45 (d, J = 0.8 Hz, 1H), 8.75-8.72 (m, 1H), 8.54 - 8.49 (m, 3H), 8.26-8.26 (m, 1H), 8.258.17־ (m, 1H), 7.84 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.39-7.36 (m, 1H), 4.97 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.23 - 4.21 (m, 2H), 3.68 - 3.66 (m, 2H) ppm.
Step 5. Preparation of $-[[2-[62)]־R)-2-methyimorpholm-4-yl]-2-pyndyfH,6-riaphthyridm7־- yl]methyl]-1,1־dioxo-3,5-dihydro-2H-4,1A6-benzoxathiepine-8-carboxamide (37) To a mixture ofN-[[2-(6-fluoro-2-pyridyl)-1,6-naphthyridin-7-ylmethyl-1,1-dioxo-3,5-dihydro- 2H- 4,1A6-benzoxathiepine-8-carboxamide (20 mg, 0.0418 mmol) and (2R)-2-methyl morpholine;hydrochloride (17.26 mg, 125.39 pmol) in DMSO (1 mL) was added DIEA (27.0 mg, 0.2mmol). The mixture was stirred at 120 °C for 16 h. Then the mixture was poured into Sat.NaHCOs (mL) and was extracted with EA (10.0 mL x 3). The combined organics were washed with brine (20.0 mL), dried over N32SO4, filtered and the filtrate was evaporated to dryness. The residue was purified by prep- HPLC (column: Shim-pack C18 150*25*10um;mobile phase: [water(0.225%FA)-ACN];B%: 38%- 58%,10min) and the eluent was concentrated under vacuum to remove the MeCN. The residue was lyophilized to give A/-[[2-[6-[(2R)-2-methylmorpholin-4-yl]-2-pyridyl]-1,6-naphthyridin-7-yl]methyl]-1 ,1- dioxo-3,5-dihydro-2H-4,1A6-benzoxathiepine-8-carboxamide (15.89 mg, 26.24 pmol, 63% yield, FA) as a yellow solid.LCMS (ESI) m/z: [M+Hp = 560.3.NMR (400 MHz, DMSO-ds) 5 = 9.65-9.62 (m, 1H), 9.40 (s, 1H), 8.68-8.61 (m, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 8.28-8.25 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.73 (m, 2H), 7.03 (d, J 221 WO 2022/103899 PCT/US2021/058865 = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.30 - 4.22 (m, 4H), 3.99-3.96 (m, 1H), 3.70 - 3.(m, 4H), 2.94 - 2.87 (m, 1H), 2.62-2.56 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H) ppm.The following examples in Table 3 were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 3.
Table 3. Compounds of the Invention # LCMS (m/z) 1H NMR 225 560.3 1H NMR (400 MHz, DMSO-ds) 6 = 9.65-9.62 (m, 1H), 9.40 (s, 1H), 8.68-8.61 (m, 2H), 8.54 (d,J=2.0 Hz, 1H), 8.46 (s, 1H), 8.28-8.25 (m, 1H), 7.92 (d, J =72 Hz, 1H), 7.(s, 1H), 7.77 - 7.73 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.30 - 4.22 (m, 4H), 3.99-3.96 (m, 1H), 3.70 - 3.58 (m, 4H), 2.94 - 2.87 (m, 1H), 2.62-2.56 (m, 1H), 1.22 (d, J = 6.0 Hz, 3H) ppm. 224 548.3 1H NMR (400 MHz, DMSO-ds) 6 = 9.64 - 9.61 (m, 1H), 9.39 (s, 1H), 8.67 (s, 2H), 8.(d, J = 1.6 Hz, 1H), 8.43 (s, 1H), 8.27-8.25 (m, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.75 - 7.69 (m, 2H), 6.69 (d, J = 8.0 Hz, 1H), 5.56 - 5.42 (m, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.93 - 3.74 (m, 3H), 3.69 - 3.67 (m, 2H), 3.58-3.51 (m, 1H), 2.53 (brs, 1H), 2.28-2.16 (m, 1H) ppm. 223 560.2 1H NMR (400 MHz, MeOD) 6 = 9.33 (s, 1H), 8.72 - 8.56 (m, 3H), 8.23 - 8.20 (m, 1H), 7.99 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.80 - 7.71 (m, 1H), 7.64 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H), 4.94 (s, 2H), 4.40 - 4.20 (m, 4H), 4.06 - 4.02 (m, 1H), 3.81 - 3.67 (m, 2H), 3.57 - 3.50 (m, 2H), 3.03 - 2.95 (m, 1H), 2.70 - 2.61 (m, 1H), 1.28 (d, J = 6.4 Hz, 3H) ppm. 222 548.2 ؛H NMR (400 MHz, DMSO-ds) 6 = 9.65 - 9.62 (m, 1H), 9.39 (s, 1H), 8.67 (s, 2H), 8.(d, J = 1.6 Hz, 1H), 8.36 (br s, 1H), 8.28 - 8.25 (m, 1H), 7.89 - 7.78 (m, 2H), 7.77 - 7.(m, 2H), 6.69 (d, J = 8.4 Hz, 1H), 5.60 - 5.40 (m, 1H), 4.98 (s, 2H), 4.82 (br d, J = 5.Hz, 2H), 4.28 - 4.17 (m, 2H), 3.94 - 3.83 (m, 1H), 3.81 - 3.65 (m, 4H), 3.58 - 3.51 (m, 1H), 2.54 (brs, 1H), 2.29 - 2.13 (m, 1H) ppm. 221 560.3 1H NMR (400 MHz, DMSO-d6) 6= 9.69 - 9.57 (m, 1H), 9.39 (s, 1H), 8.69 - 8.63 (m, 1H), 8.62 - 8.58 (m, 1H), 8.54 (s, 1H), 8.30 - 8.22 (m, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.77 - 7.65 (m, 2H), 6.54 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 - 4.81 (m, 2H), 4.29 - 4.18 (m, 2H), 4.11 (s, 2H), 3.85 - 3.75 (m, 2H), 3.72 - 3.65 (m, 2H), 3.57 - 3.56 (m, 2H), 3.30 ( s, 3H), 3.03 - 2.95 (m, 1H) ppm. 220 530.3 1H NMR (400 MHz, DMSO-d6) 5= 9.64-9.63 (m, 1H), 9.38 (s, 1H), 8.65 (s, 2H), 8.(d, J = 1.6 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.83 - 7.77 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.67 (d, J= 8.4 Hz, 1H), 6.61 (d, J= 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J= 5.6 Hz, 2H), 4.29 -4.17 (m, 2H), 3.71 - 3.65 (m, 2H), 3.53 - 3.51 (m, 4H), 2.05 - 1.94 (m, 4H) ppm. 222 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 216 574.2 1H NMR(400 MHz, DMSO-de) 6= 9.64-9.61 (m, 1H), 9.39 (s, 1H), 8.67 - 8.60 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.43(s, 1H), 8.27-8.25 (m, 1H), 7.89 -7.79 (m, 4H), 7.01 (d, J = 8.8 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 5.4 Hz, 2H), 4.24 - 4.21 (m, 2H), 4.10-4.06 (m, 2H), 3.75 - 3.66 (m, 4H), 3.38 - 3.37 (m, 2H), 1.25 -1.18 (m,6H)ppmChiral SFC: OJ-3-MeOH(DEA)-40-3mL-35T.lcm, Rt= 1.462 mins, ee% = 100 %. 215 574.4 1H NMR (400 MHz, DMSO-d6) 6 =9.64 - 9.61 (m, 1H), 9.39 (s, 1H), 8.69 - 8.59 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.45 (s, 1H), 8.27 - 8.25 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.74 - 7.70 (m, 2H), 7.01 (d, J= 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 6.0 Hz, 2H), 4.24 - 4.20 (m, 2H), 4.10 - 4.06 (m, 2H), 3.76 - 3.67 (m, 4H), 3.38 (s, 2H), 1.21 (d, J = 6.4 Hz, 6H) ppmChiral SFC: IC-3-MeOH+ACN(DEA)-50-5min-3mL-35T. Icm; RT=3.169 min; ee%~1 00%, 202 566.2 ,H NMR (400 MHz, DMSO-ds) 6 = 9.71 - 9.56 (m, 1H), 9.40 (s, 1H), 8.67 (s, 2H), 8.(d, J = 1.6 Hz, 1H), 8.31 - 8.19 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.80 - 7.71 (m, 2H), 6.74 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (br d, J = 5.6 Hz, 2H), 4.28 - 4.18 (m, 2H), 4.09 - 3.95 (m, 2H), 3.80 - 3.72 (m, 2H), 3.71 - 3.61 (m, 2H), 2.68 - 2.(m, 2H) ppm. 201 560.3 ؛H NMR (400 MHz, DMSO) 6 = 9.66 - 9.56 (m, 1H), 9.41 - 9.34 (m, 1H), 8.66 (s, 2H), 8.54 (d, J= 1.6 Hz, 1H), 8.29 - 8.24 (m, 1H), 8.14 - 8.12 (m, 1H), 7.83 - 7.79 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.71 - 7.65 (m, 1H), 6.63 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.29 - 4.20 (m, 2H), 4.16 - 4.09 (m, 1H), 3.72 - 3.66 (m, 2H), 3.65 - 3.59 (m. 3H), 3.54 - 3.46 (m, 1H), 3.30 (s, 3H), 2.15 - 2.06 (m, 2H) ppm. SFC: AD-3-EIOH (DEA)-60-3mL-5min-35T.icm, Rt=3.999 mins, ee% value = 100%. 20Q 560.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.61 (m, 1H), 9.38 (s, 1H), 8.65 (s, 2H), 8.(d, 1.6 Hz, 1H), 8.27 - 8.25 (m, 1H),7.82 - 7.80 (m, 2H), 7.74 (d, 7.6 Hz, 1H),7.69-7.67 (m, 1H), 6.63 (d, J= 8.0 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J= 5.6 Hz, 2H),4.- 4.21 (m, 2H), 4.12 - 4.10 (m, 1H), 3.72 - 3.66 (m, 2H), 3.69 - 3.62(m, 3H), 3.50 (d, J = 9.6 Hz, 1H), 3.29 (s, 3H), 2.13 - 2.08 (m, 2H) ppm.Chiral SFC: AD-3-EIOH (DEA)-6Q-3 mL-5 min-35TJcm. Ri = 3.435 min, ee % = 1%. 308 580.2 1H NMR (400 MHz, DMSO-ds) 6 = 9.71 - 9.58 (m, 1H), 9.40 (d, J= 0.8 Hz, 1H), 8.73 - 8.65 (m, 1H), 8.64 - 8.58 (m, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.43 (s, 1H), 8.31 - 8.22 (m, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.70 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 6.0 Hz, 2H), 4.28 - 4.18 (m, 2H), 4.14 - 4.00 (m, 2H), 3.84 - 3.61 (m, 4H), 2.19- 2.09 (m, 2H), 1.85 - 1.77 (m, 2H) ppm. 223 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 186 562.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.61 (m, 1H), 9.40 (s, 1H), 8.7Q - 8.64 (m, 1H), 8.64 - 8.58 (m, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.88 (d, J = 7.Hz, 1H), 7.81 (s, 1H), 7.77 - 7.70 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 5.05 - 4.79 (m, 4H), 4.28 -4.19 (m, 2H), 3.97 - 3.84 (m, 2H), 3.73 - 3.56 (m, 4H), 2.05 - 1.93 (m, 2H), 1.-1.71 (m, 2H) ppm. 184 580.1 1H NMR (400 MHz, DMSO-d8) 6 = 9.64 (s, 1H), 9.40 (s, 1H), 8.69 - 8.60 (m, 2H), 8.(d, J = 2.0 Hz, 1H), 8.50 - 8.46 (m, 1H), 8.27 - 8.25 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.79 - 7.71 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 5.01 - 4.96 (m, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.87 - 3.81 (m, 4H), 3.71 - 3.64 (m, 2H), 2.12 - 2.02 (m, 4H) ppm. 181 560.4 ؛H NMR (400 MHz, DMSO-ds) 6 = 9.64 - 9.63 (m, 1H), 9.39 (s, 1H), 8.69 - 8.57 (m, 2H), 8.54 (d, J= 1.6 Hz, 1H), 8.26 - 8.25 (m, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.72 (m, 2H), 6.96 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.53 - 4.43 (m, 1H), 4.27 - 4.19 (m, 2H), 4.09 - 4.08 (m, 1H), 4.01 -3.97 (m, 1H), 3.82- 3.75 (m, 1H), 3.73 - 3.64 (m, 3H), 3.54 - 3.53 (m, 1H), 3.16 - 3.15 (m, 1H), 1.(d, J = 6.8 Hz, 3H) ppm.Chiral SFC: AD-3-MeOH+CAN (DEA)-50-3mL-35TJcm; Ri = 1.023 mins. 178 560.1 ؛H NMR (400 MHz, DMSO) 6 = 9.70 - 9.58 (m, 1H), 9.42 - 9.37 (m, 1H), 8.70 - 8.(m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.31- 8.24 (m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.77 - 7.72 (m, 2H), 7.00 - 6.90 (m, 1H), 5.01 - 4.95 (m, 2H), 4.86- 4.(m, 2H), 4.52 - 4.42 (m, 1H), 4.27 - 4.20 (m, 2H), 4.13 - 3.95 (m, 2H), 3.81 - 3.75 (m, 1H), 3.73 - 3.64 (m, 3H), 3.58 -3.50 (m, 1H), 3.20 - 3.11 (m, 1H), 1.19 (d, J = 6.4 Hz, 3H) ppm.SFC: AD-3-EIOH (DEA)-60-3mL-5min-35T.lcm, Rt=2.356 mins, ee % value = 100 %. 174 574.2 1H NMR (400 MHz, DMSO-ds) 0 = 9.64-9.62 (m, 1H), 9.38 (s, 1H), 8.67 - 8.65 (m, 1H), 8.61 - 8.59 (m, 1H), 8.53 (d, J =1.6 Hz, 1H), 8.46 - 8.41 (m, 1H), 8.26 (s , 1H), 7.82 - 7.79 (m, 2H), 7.74 - 7.69 (m, 2H), 6.87 (d, J = 8.4 Hz,1 H), 4.98 - 4.97 (m, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.73 (br t, J = 3.2 Hz, 1H), 4.23 - 4.20 (m, 2H), 3.98 - 3.98 (m ,2H), 3.68 - 3.66 (m, 2H), 3.53 (br t, J = 11.2 Hz, 2H), 2.97 (s, 3H), 1.87 - 1.79 (m , 2H),. 63 - 1.60 ( m ,2H) ppm . ו ­ 145 548.1 1H NMR (400 MHz, DMSO-ds) 6 = 9.65 - 9.61 (m, 1H), 9.39 (d, J= 0.8 Hz, 1H), 8.68 ­8.66 (m, 1H), 8.61 - 8.59 (m, 1H), 8.54(d, J = 2.0 Hz, 1H), 8.40 (br s, 1H), 8.28 (s, 1H), 7.83 - 7.81 (m, 2H), 7.75 - 7.69 (m, 2H), 6.82 (d, J = 8.4 Hz,1 H), 4.99 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.23 (br d, J = 4.8 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 3.70 - 3.67 (m, 2H), 3.61 (t, J = 6.0 Hz, 2H), 3.28 (s, 3H), 3.15 (s, 3H) ppm. 224 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 144 559.2 1H NMR (400 MHz, DMSO-de) 6 = 9.64-9.61 (m, 1H), 9.39 (d, J = 0.8 Hz, 1H), 8.- 8.60 (m, 2H), 8.53 (d, J = 2.0 Hz, 1H), 8.27 - 8.25 (m, 1H), 8.21 (s, 1H), 7.89 - 7.(m, 1H), 7.80 (s, 1H), 7.89 - 7.74 (m, 2H), 7.01 (d, J= 8.4 Hz,1H), 4.98 (s, 2H), 4.(d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.69 - 3.67 (m, 2H), 3.64 - 3.61 (m, 4H), 2.- 2.44 (m, 4H), 2.24 (s, 3H) ppm. 228 546.3 1H NMR (400 MHz, DMSO-d6) 6= 9.64 - 9.63 (m, 1H), 9.39 (s, 1H), 8.70 - 8.64 (m, 1H), 8.63 - 8.58 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.76 - 7.68 (m, 2H), 6.58 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.44 - 4.34 (m, 1H), 4.31 - 4.19 (m, 4H), 3.88 (d, J = 3.6 Hz, 2H), 3.73 - 3.65 (m, 2H), 3.28 (s, 3H) ppm. 226 546.3 ؛H NMR (400 MHz, DMSO-ds) 6 = 9.64-9.62 (m, 1H), 9.39 (s, 1H), 8.67 - 8.61 (m, 2H), 8.53 (s, 1H), 8.27 - 8.25 (m, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.78 - 7.73 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (br d, J = 6.0 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.77 - 3.74 (m, 4H), 3.69 - 3.67 (m, 2H), 3.61 - 3.58 (m, 4H) ppm Example 4. N-((2-(4-methyl-3,4-dihydro-2H-benza[b][1,4]oxaz!n-8-yl)-1,6-naphthyridm-7-y!)methyl)- 3,5-d!hydro-2H-benzo[e][1,4]oxath!epine-8-carboxamide 1,1 -dioxide Step 4 Step 1: Preparation of4-methyl-8-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazine Pd(dppf)CI2 (32.1 mg, 0.0448 mmol) and AcOK (129 mg, 1.32 mmol) were added to a solution of 4,4,5,5-tetramethyi-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (134 mg, 0.5mmol) and 8-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.438 mmol) in dioxane (2mb). The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was diluted with H2O (20 mb) and extracted with EA (20 mb x 3). The combined organic layers were dried over anhydrous Na2SO4, 225 WO 2022/103899 PCT/US2021/058865 filtered and concentrated under reduced pressure affording the title compound (125 mg, crude) as a brown oil. LCMS (ESI) m/z: [M+H)+= 276.1 Step 2: Preparation of tert-butyl ((2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-1,6- naphthyridin-7-yi)methyS)carbamate A mixture oftert-butyl A/-[(2-chloro-1,6-naphthyridin-7-yl)methy0carbamate (100 mg, 0.340 mmol), 4-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[bj[1,4]oxazine (122 mg, 0.443 mmol), K3PO4 (217 mg, 1.02 mmol), [1,1'-Bis(d!-tert-butylphosphino)ferrocene]dichloropalladium(H) (22.2 mg, 0.340 mmol) in dioxane (1 mb) and H: Step 3: Preparation of (2-(4-methyl-3,4-dshydro-2H-benzo[b][1,4]oxazm-8-yl)-1,6-naphthynd!ri-7- yl)methanamine hydrochloride salt HCI/dioxane (4N, 750 ub) was added to a solution oftert-butyl ((2-(4-methyl-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)-1,6-naphthyridin-7-yl)methyl)carbamate (90 mg, 0.221 mmol) in dioxane (1 mb). The reaction mixture was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure. The resulting residue was washed with MTBE (5 mb x 2), filtered, and dried in vacuo affording the title compound (70 mg, 0.204 mmol) as a brown solid. LCMS (ESI) m/z: [M+H]+= 307.2.
Step 4: Preparation of N-((2-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazm-8-yl)-1,6-naphthyridin-7- yl)methyl)-3,5-dihydro-2H-benzo[e][1,4]oxathiepme-8-carboxamide 1,1 -dioxide (58) EDCI (25.2 mg, 0.131 mol), HOB (17.7 mg, 0.131 mmol), DIEA (76.2 uL, 0.438 mmol) and (2-(4- methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-1,6-naphthyridin-7-yl)methanamine hydrochloride salt (30 mg, 0.0875 mmol) were added to a solution of 2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (25.4 mg, 0.105 mmol) in DCM (0.5 mb) was added. The reaction mixture was stirred at 25°C for 2 h. The reaction mixture was diluted with H2O (5 mb) and extracted with DCM (5 mb x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reversed-phase HPLC (0.1% FA condition). The solution was concentrated under reduced pressure to remove MeCN and lyophilized affording the title compound (14.2 mg, 0.0257 mmol) as a yellow solid. LCMS (ESI) m/z: [M+H]+=: 531.2. 1H NMR (400 MHz, CD3OD) = 9.30 (s, 1H), 8.64 - 8.59 (m, 1H), 8.48 (d, J = 8.8 Hz, 1H), 8.22 - 8.20 (m, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.01 - 6.92 (m, 2H), 6.88 - 6.83 (m, 1H), 5.04 (s, 2H), 4.92 (s, 2H), 4.35 - 4.31 (m, 4H), 3.53 - 3.50 (m, 2H), 3.34 (d, J = 4.4 Hz, 2H), 2.97 - 2.92 (m, 3H) ppm. 226 WO 2022/103899 PCT/US2021/058865 The following examples in Table 4A were prepared using standard chemical manipulations and procedures similar to those used for the preparation of Example 4.
Table 4A. Compounds of the Invention. ______________________________________________________ # LCMS (m/z) 1H NMR 227 460.0 1HNMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.39 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.34 - 8.24 (m, 4H), 7.82 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.61 - 7.52 (m, 3H), 4.99 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.32 - 4.14 (m, 2H), 3.78 - 3.60 (m, 2H) ppm 307 515.2 1H NMR (400 MHz, CD:OD) 6 = 9.16 (s, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.46 - 8.33 (m, 1H), 8.27 - 8.17 (m, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.97 - 7.92 (m, 2H), 7.85 (s, 1H), 7.- 7.61 (m, 2H), 6.64 - 6.53 (m, 1H), 5.05 (s, 2H), 4.89 (br s, 2H), 4.41 - 4.28 (m, 2H), 3.57 - 3.51 (m, 2H), 3.48 - 3.43 (m, 2H), 3.09 - 2.99 (m, 2H), 2.86 (s, 3H) ppm 196 531.3 ,H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.55 (m, 1H), 9.30 (s, 1H), 8.57 - 8.50 (m, 2H), 8.28 - 8.19 (m, 2H), 7.78 - 7.71 (m, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.58 - 7.54 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.34 - 4.27 (m, 2H), 4.26 - 4.19 (m, 2H), 3.72 - 3.65 (m, 2H), 3.29 (d, J = 4.0 Hz, 2H), 2.96 (s, 3H) ppm 193 515.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.59 (m, 1H), 9.34 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.28 - 8.20 (m, 2H), 7.79 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.55- 7.53 (m, 1H), 7.38 (s, 1H), 7.20 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 5.Hz, 2H), 4.25 - 4.20 (m, 2H), 3.71 - 3.66 (m, 2H), 2.96 - 2.92 (m, 2H), 2.80 (s, 3H), 2.- 2.51 (m, 2H) ppm 189 516.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.8Q - 9.78 (m, 1H), 9.37 (s, 1H), 9.28 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 2.Q Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.36 - 7.32 (m, 1H), 7.27 - 7.26 (m, 1H), 6.59 -6.57 (m, 1H), 5.06 (s, 2H), 4.83 (d, J = 6.Q Hz, 2H), 4.31 - 4.27 (m, 2H), 3.89 (d, J = 14.4 Hz, 4H), 3.85 (s, 2H), 2.35 - 2.32 (m, 2H) ppm 249 501.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.82 - 9.79 (m, 1H), 9.38 (s, 1H), 9.29 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.45 - 7.41 (m, 1H), 7.23 (d, J =7.6 Hz, 1H), 5.07 (s, 2H), 4.84 (d, J = 5.8 Hz, 2H), 4.32 - 4.26 (m, 2H), 3.87 - 3.80 (m, 2H), 2.10 - 2.02 (m, 1H), 1.04 - 0.97 (m, 2H), 0.81 - 0.75 (m, 2H)ppm 246 513.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.36 (s, 1H), 8.72 - 8.68 (m, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 1.2 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.18 - 8.17 (m , 1H), 8.04 - 8.01 (m, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 4.90 (s, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.72 (d, J = 5.6 Hz, 2H), 2.07 - 2.05 (m, 1H), 1.02 - 0.99 (m, 2H), 0.78 - 0.76 (m, 2H) ppm. 227 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 262 522.2 1H NMR (400 MHz, DMSO-de) 6= 9.70 (s, 1H), 9.67 - 9.64 (m, 1H), 9.48 (s, 1H), 8.(s, 1H), 8.80-8.76 (m, 1H), 8.65-8.63(m, 1H), 8.53 (d, J= 1.6 Hz, 1H),8.47(s,1H), 8.27- 8.25 (m, 1H), 7.91 (s, 1H), 7.74 (d, J = 7.6 Hz,1H), 4.98 (s, 2H), 4.84 (d, J - 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.69 - 3.66 (m, 2H), 1.89 - 1.77 (m, 6H) ppm. 209 530.2 1H NMR (400 MHz, DMSO-de) 5 = 10.03 (s, 1H), 9.699.65־ (m, 1H), 9.52 (s, 1H), 9.(s, 1H), 8.84 (d, J =8.4 Hz, 1H), 8.61 - 8.52 (m, 2H), 8.28- 8.25 (m, 1H), 7.94 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.86 (d, J = 5.6 Hz, 2H), 4.27 - 4.20 (m, 2H), 3.- 3.66 (m, 2H) ppm. 305 502.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.45 (s, 2H), 8.78 (s, 1H), 8.(d, J = 8.8 Hz, 1H), 8.56-8.53 (m, 2H), 8.27- 8.25 (m, 1H), 7.88 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.69 - 3.66 (m, 2H), 3.30 (s, 3H), 2.36-2.34 (m, 1H), 1.16-1.14 (m, 4H) ppm. 182 567.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.69 - 9.68 (m, 1H), 9.43 (s, 1H), 8.94 (s, 1H), 8.(d, J = 8.4 Hz, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 8.- 8.30 (m, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.86 (s, 1H), 4.83 (d, J = 5.6 Hz, 2H), 4.40 (br d, J = 11.2 Hz, 2H), 3.73 - 3.66 (m, 2H), 3.43 (s, 3H), 2.62 - 2.56 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H) ppm. 163 583.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.73 - 9.71 (m, 1H), 9.44 (d, J = 0.4 Hz, 1H), 8.95 (s, 1H), 8.73 - 8.70 (m, 1H), 8.60 - 8.56 (m,2H), 8.49 - 8.44 (m, 2H), 8.10 (d, J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.83 - 7.56 (m, 1H), 4.85 (d, J = 5.6 Hz, 2H), 4.41 (br d, J = 11.2 Hz, 2H), 3.71 - 3.66 (m, 2H), 3.38 (s, 3H), 2.62 - 2.56 (m, 2H), 1.22 (d, J = 6.4 Hz, 6H) ppm. 230 501.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.78 - 9.74 (m, 1H), 9.45 (d, J = 2.0 Hz, 2H), 9.(d, J = 2.0 Hz, 1H), 8.79 (s, 1H), 8.77 - 8.72 (m, 2H), 8.55 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 4.85 (d, J = 5.6 Hz, 2H), 3.56 - 3.51 (m, 2H), 3.40 - 3.35 (m, 2H), 2.39 - 2.33 (m, 1H), 2.22 - 2.12 (m, 2H), 1.91 -1.75 (m, 2H), 1.18 - 1.13 (m, 4H) ppm. 236 502.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.51 - 9.41 (m, 2H), 8.79 (s, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.51 - 8.48 (m, 1H), 8.24 - 8.(m, 7.8 Hz, 1H), 7.87 (s, 1H) , 7.66 (d, J = 7.9 Hz, 1H), 5.00 (s, 2H), 4.84 (d, J = 5.6 Hz, 2H), 4.09 - 3.97 (m, 2H), 3.48 - 3.41 (m, 2H), 2.34 (s, 1H), 1.22 -1.10 (m, 4H) ppm 269 508.3 ؛H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.44 (s, 2H), 8.78 (s, 1H), 8.(d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.8 Hz,1 H), 8.50 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 7.89 (s, 1H), 4.83 (d, J = 6.0 Hz, 2H), 3.34 (s, 3H), 2.75 (s, 3H), 2.35 - 2.32 (m, 1H), 1.15-1.14 (m, 4H) ppm. 272 512.01H NMR (400 MHz, DMSO-de) 6 = 9.73 (brs, 1H), 9.49 - 9.39 (m, 2H), 8.83 - 8.69 (m, 2H), 8.55 (d, J = 8.8 Hz, 1H), 8.47 (s, 1H), 8.36 (d, J = 9.2 Hz, 1H), 7.97 - 7.86 (m, 1H), 4.83 (d, J = 5.6 Hz, 2H), 3.46 (s, 3H), 2.37 - 2.31 (m, 1H), 1.15 (d, J = 6.0 Hz, 4H) ppm. 228 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 298 475.3 1H NMR (400 MHz, DMSO-de) 6 = 9.74 - 9.71 (m, 1H), 9.45 (d, J = 2.0 Hz, 2H), 9.28 (d, J = 2.0 Hz, 1H), 8.79 (s, 1H), 8.75- 8.73 (m, 2H), 8.55 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 4.85 (d, J = 5.6 Hz, 2H), 3.38 (s, 3H), 2.91 (s, 3H), 2.39 - 2.34 (m, 1H), 1.18 -1.13 (m, 4H) ppm. 302 502.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.52 (m, 1H), 9.48 - 9.38 (m, 2H), 8.80 - 8.(m, 1H), 8.77 - 8.73 (m, 1H), 8.58 -8.53 (m, 1H), 8.49 - 8.46 (m, 1H), 8.31 - 8.22 (m, 1H), 7.90 - 7.78 (m, 1H), 7.49 - 7.31 (m, 1H), 4.86 - 4.78 (m, 2H), 4.32 - 4.24(m, 2H), 3.66 - 3.59 (m, 2H), 2.38 - 2.32 (m, 1H), 2.32 - 2.24 (m, 2H), 1.18-1.13 (m, 4H) ppm. 288 523.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.64 (m, 1H), 9.44 (s, 2H), 8.78 (s, 1H), 8.(d, J = 8.8 Hz, 1H), 8.55 (d, J = 8.4 Hz,1 H), 8.51 (d, J = 2.0 Hz, 1H), 8.25 - 8.22 (m, 1H), 7.90 - 7.87 (m, 2H), 4.83 (d, J = 5.6 Hz, 2H), 2.84 (s, 6H), 2.34 (d, J = 6.8 Hz, 1H), 1.16 - 1.14 (m, 4H) ppm. 188 513.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.36 (s, 1H), 8.72 - 8.68 (m, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 1.2 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.18 - 8.17 (m, 1H), 8.04 - 8.01 (m, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 4.90 (s, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.72 (d, J = 5.6 Hz, 2H), 2.07 - 2.05 (m, 1H), 1.02 - 0.99 (m, 2H), 0.78 - 0.76 (m, 2H) ppm. 197 530.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.61 (m, 1H), 9.39 (s, 1H), 8.69 - 8.64 (m, 1H), 8.62 - 8.58 (m, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.27 - 8.26 (m, 1H), 7.87 (d, J = 7.Hz, 1H), 7.82 (s, 1H), 7.77 - 7.67 (m, 2H), 6.53 (d, J = 8.0 Hz, 1H), 4.96 (s, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.31 -4.27 (m, 1H), 4.12 - 3.98 (m, 5H), 3.71 -3.59 (m, 1H), 2.41 - 2.35 (m, 2H), 1.16 (d, J = 7.2 Hz, 3H) ppm.Chiral SFC: AD-3-IPA+CAN (DEA)-40-5min-3mL-35T.lcm; Rt = 2.838 mins, ee %=100.00 %. 199 530.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.62 (m, 1H), 9.39 (s, 1H), 8.68 - 8.64 (m, 1H), 8.62 - 8.58 (m, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.28 - 8.26 (m, 1H), 7.87 (d, J = 7.Hz, 1H), 7.82 (s, 1H), 7.77 - 7.67 (m, 2H), 6.53 (d, J = 7.6 Hz, 1H), 4.96 (s, 2H), 4.82 (d, J = 6.0 Hz, 2H), 4.31 -4.27 (m, 1H), 4.12 - 3.97 (m, 5H), 3.70 - 3.61 (m, 1H), 2.41 - 2.36 (m, 2H), 1.16 (d, J = 6.8 Hz, 3H) ppm.Chiral SFC: AD-3-IPA+CAN (DEA)-40-5min-3mL-35T.lcm; Rt = 3.552 mins. 287 520.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.73 - 9.70 (m, 1H), 9.45 (s, 2H), 8.78 - 8.73 (m, 2H), 8.55 (d, J = 8.4 Hz, 1H), 8.41-8.40 (m, 1H), 8.19-8.16 (m, 1H), 7.90 (s, 1H), 5.(s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.77 -3.75 (m, 2H), 2.38 - 2.33 (m, 1H), 1.16 -1.14 (m, 4H) ppm. 187 536.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.74 - 9.71 (m, 1H), 9.45(8, 2H), 8.78 - 8.73 (m, 2H), 8.57 - 8.50 (m, 2H), 8.42 - 8.40 (m, 2H), 7.91 (s, 1H), 5.20 (s, 2H), 4.83 (d, J = 5.Hz, 2H), 4.24 - 4.22 (m, 2H), 3.79 - 3.77 (m, 2H), 2.38 - 2.33 (m, 1H), 1.16 -1.14 (m, 4H) ppm 229 WO 2022/103899 PCT/US2021/058865 # LCMS (m/z) 1H NMR 293 501.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.52 (m, 1H), 9.45 (d, J= 1.2 Hz, 2H), 8.(s, 1H), 8.77 - 8.71 (m, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.49 - 8.37 (m, 1H), 8.19- 8.(m, 1H), 7.84 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 4.82 (d, J = 6.0 Hz, 2H), 3.41 (br s, 2H), 3.29 - 3.28 (m, 1H), 3.28 - 3.23 (m, 2H), 2.41 - 2.29 (m, 1H), 1.73 (br s, 2H), 1.20 - 1.(m, 4H) ppm. 297 515.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.50 (m, 1H), 9.44 (s, 2H), 8.81 - 8.69 (m, 2H), 8.53 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 1.6 Hz, 1H), 8.22 - 8.08 (m, 1H), 7.87 (s, 1H), 7.61 (d, J= 8.0 Hz, 1H), 4.81 (brd, 5.6 Hz, 2H), 3.82 - 3.50 (m, 2H), 3.24 (br s, 2H), 2.57 (s, 3H), 2.40 - 2.25 (m, 1H), 1.79 (br d, J = 5.2 Hz, 2H), 1.22 - 1.09 (m, 4H) ppm. 252 536.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 (s, 1H), 9.39 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.53 (d, J 1.6 Hz, 1H), 8.34-8.17 (m, 4H), 7.82 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.(d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.25 - 4.20 (m, 2H), 3.69 - 3.66 (m, 2H), 3.11 (s, 1H), 2.14-1.98 (m, 2H) ppm.Chiral SFC: IG-3-MeOH+ACN(DEA)-60-3ML-7MIN-35T.lcm, Rt= 3.596 min, ee %= 1%. 251 536.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 (s, 1H), 9.39 (s, 1H), 8.66 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.34 - 8.16 (m, 4H), 7.82 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.48 - 7.40 (m, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.22 (d, J = 5.6 Hz, 2H), 3.- 3.66 (m, 2H), 3.11 (s, 1H), 2.17-1.96 (m, 2H) ppm.Chiral SFC: IG-3-MeOH+ACN(DEA)-60-3ML-7MIN-35T. ؛cm, Rt= 4.550 min, ee %= 96.31 %. 286 501.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.56 (m, 1H), 9.45 - 9.45 (m, 2H), 8.79 (s, 1H), 8.76-8.74 (m, 1H), 8.58 (d, J= 1.8 Hz, 1H), 8.56 (d, 0=8.8 Hz, 1H), 8.18-8.(m, 1H), 7.86 (s, 1H), 7.65 (d, J= 8.0 Hz, 1H), 5.11 (d, J= 13.2 Hz, 1H), 4.92 (d, J = 13.2 Hz, 1H), 4.84 (d, 5.6 Hz, 2H), 4.76 (s, 1H), 4.26 - 4.19 (m, 2H), 3.44-3.41 (m,2H), 2.39 - 2.35 (m, 1H), 1.16 -1.14 (m, 4H) ppm.
The following examples in Table 4B were prepared using standard chemical manipulations and procedures similar to those used above.
Table 4B. Compounds of the Invention.
# LCMS (ESi/M+H) 1H NMR 309 516.1 1H NMR (400 MHz, DMSO-d6) 5 9.75 (t, J = 5.8 Hz, 1H), 8.90 (dd, J = 9.1, 1.0 Hz, 1H), 8.52 (dd, J = 5.5, 3.6 Hz, 2H), 8.25 (dd, J = 7.8, 1.9 Hz, 1H), 8.17 (d, J = 1.Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.66-7.58 (m, 1H), 7.44-7.26 (m, 2H), 6.68-6.(m, 1H), 5.12 (d, J = 5.7 Hz, 2H), 4.97 (s, 2H), 4.28-4.21 (m, 2H), 3.91 (t, J = 7.Hz, 4H), 3.72-3.65 (m, 2H), 2.40-2.29 (m, 2H). 230 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 310 574.3 1H NMR (400 MHz, Methanol-d4) 5 8.79 (d, J = 9.0 Hz, 1H), 8.58 (d, J = 1.9 Hz, 1H), 8.41 (d, J = 9.1 Hz, 1H), 8.27-8.14 (m, 2H), 7.86-7.81 (m, 1H), 7.69-7.58 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.16 (dd, J = 8.3, 2.5 Hz, 1H), 5.19 (s, 2H), 5.02 (s, 2H), 4.37-4.28 (m, 2H), 3.86-3.75 (m, 2H), 3.65 (dd, 2H), 3.58-3.48 (m, 2H), 2.(dd, J = 11.9, 10.3 Hz, 2H), 1.23 (d, J = 6.3 Hz, 6H). 311 574.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.31 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.(d, J = 1.8 Hz, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.48 (s, 1H), 8.24 - 8.22 (m, 1H), 7.(s, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.77 - 7.63 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H), 5.(s, 2H), 4.95 (s, 2H), 4.40 - 4.33 (m, 2H), 3.62 - 3.53 (m, 3H), 3.44 (s, 3H), 3.36 (s, 1H), 3.28 (s, 3H), 2.53 - 2.51 (m, 1H), 1.43 -1.41 (m, 1H), 1.02 - 0.89 (m, 2H) ppm 312 574.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.29 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.(d, J = 1.8 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.47 (s, 1H), 8.22 8.20 (m, 1H), 7.(s, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.73 - 7.61 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 5.(s, 2H), 4.93 (s, 2H), 4.41 - 4.30 (m, 2H), 3.60 - 3.50 (m, 3H), 3.42 (s, 3H), 3.34 (br s, 1H), 3.26 (s, 3H), 2.51 - 2.50 (m, 1H), 1.46 - 1.37 (m, 1H), 0.99 - 0.89 (m, 2H) ppm 313 589.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.60 (m, 1H), 9.36 (s, 1H), 8.54 - 8.49 (m, 2H), 8.43 (s, 1H), 8.24 - 8.22 (m, 1H), 7.88 - 7.70 (m, 3H), 7.09 - 6.96 (m, 3H), 4.(s, 2H), 4.80 (br d, J = 5.6 Hz, 2H), 4.26 - 4.17 (m, 2H), 4.11- 4.09 (m, 2H), 3.70 - 3.64 (m, 2H), 3.57 - 3.52 (m, 2H), 3.41 - 3.40 (m, 5H), 3.29 (s, 3H), 2.01 - 1.91 (m, 2H) ppm 314 578.4 1H NMR (400 MHz, METHANOL-d4) 5 = 9.30 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.(d, J = 1.6 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.22 - 8.20 (m, 1H), 8.00 - 7.89 (m, 2H), 7.79 - 7.69 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 4.82 - 4.69 (m, 4H), 4.46 - 4.31 (m, 4H), 3.60 - 3.49 (m, 2H), 3.(s, 3H) ppm 315 530.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60-9.57 (m, 1H), 9.05 (s, 1H), 8.54 (d, J = 1.Hz, 1H), 8.27-8.24 (m , 1H), 8.22 (s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 9.Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.48 - 7.47 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 4.(s, 2H), 4.74 (brd, J = 6.0 Hz, 2H), 4.24-4.21 (m, 2H), 4.13-4.10 (m, 2H), 3.70-3.(m, 2H), 2.78-2.76 (m, 2H), 2.35 (s, 3H), 1.96-1.90 (m, 2H) ppm 316 554.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.68 - 9.57 (m, 1H), 9.37 (s, 1H), 8.58 - 8.50 (m, 2H), 8.28 - 8.23 (m, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.83 - 7.70 (m, 3H), 7.19 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.53 - 6.15 (m, 1H), 4.97 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.29 - 4.18 (m, 2H), 3.87 (s, 3H), 3.73 - 3.63 (m, 2H), 3.29 - 3.22 (m, 2H) ppm 231 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 317 576.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.39 (s, 1H), 8.71 - 8.57 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.85 - 7.78 (m, 2H), 7.77 - 7.(m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 - 4.(m, 2H), 4.25 - 4.20 (m, 2H), 3.71 - 3.66 (m, 2H), 3.24 - 3.05 (m, 2H), 1.95 - 1.(m, 4H), 1.45 - 1.36 (m, 3H) ppm 318 576.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.39 (s, 1H), 8.71 - 8.57 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.85 - 7.78 (m, 2H), 7.77 - 7.(m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 - 4.(m, 2H), 4.25 - 4.20 (m, 2H), 3.71 - 3.66 (m, 2H), 3.24 - 3.05 (m, 2H), 1.95 -1.(m, 4H), 1.45 - 1.36 (m, 3H) ppm 319 588.5 1H NMR (400 MHz, METHANOL-d4) 6 = 9.22 - 9.16 (m, 1H), 8.56 - 8.43 (m, 3H), 8.15-8.05 (m, 1H), 7.85- 7.82 (m, 1H), 7.81 -7.77 (m, 1H), 7.65-7.59 (m, 1H), 7.50 - 7.46 (m, 1H), 6.87 - 6.82 (m, 1H), 4.82 (br s, 2H), 4.73 - 4.66 (m, 1H), 4.30 - 4.16 (m, 3H), 3.77 - 3.59 (m, 4H), 3.17 - 3.06 (m, 1H), 2.52 - 2.39 (m, 2H), 1.53 - 1.48 (m, 3H), 1.21 -1.18 (m, 6H) ppm 320 554.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.70 - 9.57 (m, 1H), 9.40 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.43 (s, 1H), 8.34 - 8.21 (m, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.26 - 6.95 (m, 1H), 4.95 (s, 2H), 4.81 (brd, J = 6.Hz, 2H), 4.37 - 4.22 (m, 1H), 4.08 - 3.96 (m, 1H), 3.91 (s, 3H), 3.72 - 3.58 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H) ppm 321 556.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.70 - 9.60 (m, 1H), 9.39 (s, 1H), 8.69 - 8.58 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.42 (s, 1H), 8.31 - 8.23 (m, 1H), 7.83 - 7.78 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.70 - 7.64 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (br d, J = 5.6 Hz, 2H), 4.31 - 4.16 (m, 2H), 4.05 - 3.96 (m, 1H), 3.93 - 3.85 (m, 1H), 3.74-3.62 (m, 2H), 3.55-3.45 (m, 2H), 2.17-1.99 (m, 1H), 1.91 - 1.76 (m, 1H), 1.21 -1.05 (m, 2H), 0.70 - 0.55 (m, 1H), 0.35 - 0.17 (m, 1H) ppm 322 556.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.70 - 9.60 (m, 1H), 9.40 (s, 1H), 8.69 - 8.58 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.42 (s, 1H), 8.31 - 8.22 (m, 1H), 7.83- 7.78 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.70 - 7.64 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (br d, J = 5.6 Hz, 2H), 4.31 - 4.15 (m, 2H), 4.05 - 3.95 (m, 1H), 3.93 - 3.85 (m, 1H), 3.74 - 3.62 (m, 2H), 3.55 - 3.45 (m, 2H), 2.17 - 1.99 (m, 1H), 1.91-1.77 (m, 1H), 1.21-1.05 (m, 2H), 0.70 - 0.55 (m, 1H), 0.35 -0.17 (m, 1H) ppm 323 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.64-9.61 (m, 1H), 9.38 (s, 1H), 8.71 - 8.64 (m, 1H), 8.62 - 8.57 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.86 - 7.(m, 2H), 7.77 - 7.65 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 6.Hz, 2H), 4.29 - 4.18 (m, 2H), 3.99 (s, 2H), 3.71 - 3.65 (m, 2H), 3.20 (s, 3H), 3.15 (s, 3H), 0.77 - 0.66 (m, 4H) ppm 232 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 324 572.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.56 (m, 1H), 9.40 (s, 1H), 8.72 - 8.56 (m, 2H), 8.50 - 8.39 (m, 1H), 8.21 -8.11 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.83 - 7.(m, 2H), 7.58 - 7.48 (m, 1H), 7.08 - 6.99 (m, 1H), 4.87 - 4.73 (m, 2H), 4.40 - 4.(m, 2H), 3.72- 3.63 (m, 3H), 3.12 (brd, J = 4.2 Hz, 2H), 2.66 (brs, 2H), 2.32-2.(m, 2H), 1.37 (br d,J= 6.8 Hz, 3H), 1.22 (br d, J = 6.2 Hz, 6H) ppm 325 602.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.45 - 9.33 (m, 2H), 8.71 - 8.58 (m, 2H), 8.(d, J = 1.6 Hz, 1H), 8.46 (br s, 1H), 8.28 - 8.25 (m, 1H), 7.97 - 7.88 (m, 2H), 7.81 - 7.68 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 5.52 - 5.38 (m, 1H), 4.96 (s, 2H), 4.41 - 4.(m, 3H), 4.02 - 4.00 (m, 1H), 3.74 - 3.59 (m, 3H), 2.62 (br s, 2H), 1.66 (br d, J = 7.Hz, 3H), 1.22 (d, J = 6.2 Hz, 6H), 1.16 (d, J = 7.0 Hz, 3H) ppm 326 589.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.63-9.60 (m, 1H), 9.34 (s, 1H), 8.52-8.49 (m, 2H), 8.38 (s, 1H), 8.25-8.23 (m, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 6.96-6.81 (m, 3H), 4.97 (s, 2H), 4.81 (brd, J = 5.2 Hz, 2H), 4.23- 4.20 (m, 2H), 4.05-4.04(m, 2H), 3.68 - 3.65 (m, 2H), 3.62 (br d, J = 6.4 Hz, 1H), 3.56-3.50 (m, 4H), 3.28 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H) ppm 327 561.1 1H NMR (400 MHz, DMSO-d6) 0 = 9.68 - 9.65 (m, 1H), 9.45 (s, 1H), 8.78 (d, J = 8.8 Hz, 1H), 8.64 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.33 - 8.24 (m, 2H), 8.15 - 7.71 (m, 3H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.29 - 4.16 (m, 2H), 3.75 - 3.63 (m, 2H) ppm 328 560.3 1H NMR (400 MHz, METHANOL-d4) 5 = 9.35 (s, 1H), 8.70 - 8.60 (m, 3H), 8.49 (br s, 1H), 8.31 (d, J = 7.4 Hz, 1H), 8.24 - 8.22 (m, 1H), 7.99 (s, 1H), 7.94 - 7.92 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.90 - 5.88 (m, 1H), 5.07 (s, 2H), 4.95 (s, 2H), 4.40 - 4.33 (m, 2H), 3.71 - 3.53 (m, 5H), 3.31 - 3.26 (m, 1H), 2.(s, 3H), 2.78 - 2.65 (m, 1H), 2.39 - 2.37 (m, 1H) ppm 329 541.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.62 (m, 1H), 9.43 (s, 1H), 8.65 (d, J = 8.6 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.28 - 8.18 (m, 2H), 7.81 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.13-6.83 (m, 1H), 4.98 (s, 2H), 4.82 (brd, J = 6.0 Hz, 2H), 4.27 - 4.18 (m, 2H), 4.02 (s, 3H), 3.74 - 3.62 (m, 2H) ppm 330 519.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.68 - 9.58 (m, 1H), 9.42 (s, 1H), 8.74 - 8.68 (m, 1H), 8.67 - 8.60 (m, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.29 - 8.28 (m, 1H), 8.20 (d, J = 6.8 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.85 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.83 (d, J = 6.0 Hz, 2H), 4.54 - 4.48 (m, 2H), 4.31 - 4.(m, 1H), 4.04-4.02 (m, 1H), 3.70-3.60 (m, 1H), 1.43- 1.39 (m, 3H), 1.17 (d, J = 7.2 Hz, 3H) ppm 233 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 331 515.1 1H NMR (40Q MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.41 (s, 1H), 8.7Q - 8.67 (m, 1H), 8.64 - 8.59 (m, 1H), 8.53 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.28 (d, J = 7.6 Hz, 1H), 7.87 - 7.82 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.29 (d, J = 13.2 Hz, 1H), 4.04 - 3.99 (m, 1H), 3.66 - 3.57 (m, 1H), 2.24-2.22 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 1.11-1.09 (m, 2H), 1.- 1.03 (m, 2H) ppm 332 578.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.40 (s, 1H), 8.67 (s, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.45 (brs, 1H), 8.27 - 8.25 (m, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.69 (m, 2H), 6.68 (d, J = 8.4 Hz, 1H), 5.56 -5.33 (m, 1H), 4.98 (s, 2H), 4.82 (brd, J = 5.6 Hz, 2H), 4.26 - 4.21 (m, 2H), 4.21 - 4.12 (m, 1H), 4.04 - 3.96 (m, 1H), 3.96 - 3.87 (m, 1H), 3.86 - 3.78 (m, 1H), 3.77 - 3.63 (m, 3H), 3.44 (s, 3H) ppm 333 578.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.63 - 9.61 (m, 1H), 9.40 (s, 1H), 8.67 (s, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 8.27 - 8.25 (m, 1H), 7.87 (d, J = 7.4 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.69 (m, 2H), 6.68 (d, J = 8.4 Hz, 1H), 5.54 - 5.35(m, 1H), 4.98 (s, 2H), 4.85 -4.78 (m, 2H), 4.26 - 4.22 (m, 2H), 4.21 -4.11 (m, 1H), 4.04 - 3.96 (m, 1H), 3.96 - 3.87 (m, 1H), 3.87 - 3.77 (m, 1H), 3.76 - 3.65 (m, 3H), 3.44 (s, 3H) ppm 334 602.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.71 - 9.57 (m, 1H), 9.38 (s, 1H), 8.72 - 8.50 (m, 3H), 8.44 (br d, J = 1.8 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.88 - 7.79 (m, 2H), 7.78 - 7.65 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (brd, J = 5.6 Hz, 2H), 4.- 4.66 (m, 1H), 4.26 - 4.19 (m, 2H), 3.88 - 3.78 (m, 2H), 3.68 - 3.66 (m, 2H), 3.21 (s, 3H), 2.01 -1.90 (m, 2H), 1.67 - 1.50 (m, 2H), 1.19-1.05 (m, 6H) ppm 335 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.42 (s, 1H), 8.61 (d, J =8.6 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.25 - 8.23 (m, 1H), 8.07 (d, J = 8.6 Hz, 1H),7.96 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.54 -7.41 (m, 2H), 4.97 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.27 - 4.18 (m, 2H), 3.95 (s,3H), 3.72 - 3.63 (m, 2H) ppm 336 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.69 - 9.58 (m, 1H), 9.46 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.47 - 8.41 (m, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.30 - 8.21 (m, 1H), 7.92 (s, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.(d, J = 3.6 Hz, 1H), 4.98 (s, 2H), 4.85 (d, J = 5.2 Hz, 2H), 4.60 - 4.43 (m, 2H), 4.30 - 4.17 (m, 2H), 3.79 - 3.72 (m, 2H), 3.71 - 3.63 (m, 2H), 3.24 (s, 3H) ppm 337 544.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.30 (s, 1H), 8.71 - 8.53 (m, 3H), 8.23 - 8.20 (m, 1H), 7.96 (s, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.74 - 7.61 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 5.07 - 5.03 (m, 2H), 4.94 - 4.92 (m, 2H), 4.34 - 4.33 (m, 2H), 3.89 (d, J = 6.8 Hz, 2H), 3.56 - 3.50 (m, 2H), 2.65 - 2.59 (m, 1H), 1.25 - 1.22 (m, 3H), 0.97 - 0.95 (m, 2H), 0.70 - 0.69 (m, 2H) ppm 234 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 338 562.2 1H NMR (40Q MHz, METHANOL-d4) 6 = 9.29 (s, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.(d, J = 8.8 Hz, 1H), 8.47 (s, 1H), 8.05 - 8.02 (m, 1H), 7.96 (s, 1H), 7.89 (d, J = 7.Hz, 1H), 7.71 - 7.69 (m, 1H), 7.17 (d, J = 8.4 Hz, 1H), 5.14 (s, 2H), 4.92 (s, 2H), 4.34 - 4.32 (m, 2H), 3.91 - 3.86 (m, 2H), 3.61 - 3.54 (m, 2H), 2.65 - 2.58 (m, 1H), 1.25 - 1.21 (m, 3H), 0.99 - 0.92 (m, 2H), 0.73 - 0.67 (m, 2H) ppm 339 578.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.40 (s, 1H), 8.67 (s, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.79 - 7.68 (m, 2H), 6.71 (d, J = 8.2 Hz, 1H), 5.50 - 5.27 (m, 1H), 4.98 (s, 2H), 4.(br d, J = 6.0 Hz, 2H), 4.27 -4.15 (m, 3H), 3.95 - 3.75 (m, 2H), 3.73 (br s, 2H), 3.- 3.66 (m, 2H), 3.40 (s, 3H) ppm 340 578.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.62-9.60 (m, 1H), 9.39 (s, 1H), 8.71 - 8.64 (m, 2H), 8.54 (d, J 1.6 Hz, 1H), 8.26-8.24 (m, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.68 (m, 2H), 6.70 (d, J = 8.4 Hz, 1H), 5.52 - 5.25 (m,1H), 4.98 (s, 2H), 4.82 (brd, J = 5.6 Hz, 2H), 4.28 - 4.14 (m, 3H), 3.94 - 3.75 (m, 2H), 3.72 (brs, 2H), 3.70 - 3.66 (m, 2H), 3.40 (s, 3H) ppm 341 596.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.63 - 9.61 (m, 1H), 9.39 (s, 1H), 8.71 - 8.65 (m, 1H), 8.63 - 8.56 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.26 - 8.24 (m, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.81 (s, 1H), 7.79 - 7.71 (m, 2H), 7.06 (d, J = 8.6 Hz, 1H), 4.98 (s, 2H), 4.82 (brd, J = 5.6 Hz, 2H), 4.39 (brt, J = 12.8 Hz, 2H), 4.29 - 4.17 (m, 2H), 4.07 - 3.90 (m, 4H), 3.84 - 3.82 (m, 2H), 3.74 - 3.63 (m, 2H) ppm 342 560.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.64 (m, 1H), 9.43 (s, 1H), 8.76 - 8.69 (m, 1H), 8.67 - 8.60 (m, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.28 - 8.26 (m, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.91 - 7.90 (m, 1H), 7.84 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.65 - 5.56 (m, 1H), 4.99 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.24 - 4.22 (m, 2H), 3.74 - 3.66 (m, 2H), 3.07 - 3.05 (m, 1H), 2.84 (br d, J = 8.0 Hz, 2H), 2.61 -2.54 (m, 1H), 2.48-2.43 (m, 1H), 2.39 (s, 3H), 2.01 -1.89 (m, 1H) ppm 343 540.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.44 (s, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 1.2 Hz, 1H), 8.25 - 8.23 (m, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.46 - 7.42 (m, 1H), 7.40- 7.08 (m, 1H), 4.97 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.25-4.18 (m, 2H), 3.- 3.64 (m, 2H), 3.44 (s, 3H) ppm 344 602.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 - 9.54 (m, 1H), 9.40 (s, 1H), 8.72 - 8.58 (m, 2H), 8.47 (d, J = 1.8 Hz, 1H), 8.19-8.17 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.78 - 7.67 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.81 (brd, J = 6.0 Hz, 2H), 4.(br d, J = 11.2 Hz, 2H), 3.73 - 3.61 (m, 3H), 3.46 - 3.40 (m, 4H), 3.24 (s, 3H), 2.52 - 2.52 (m, 2H), 2.31 - 2.24 (m, 2H), 1.21 (d, J = 6.2 Hz, 6H) ppm 235 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 345 576.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.32 (s, 1H), 8.69 - 8.64 (m, 2H), 8.62 - 8.57 (m, 1H), 8.47 - 8.41 (m, 1H), 8.24 - 8.22 (m, 1H), 7.98 (s, 1H), 7.83 (d, J = 7.Hz, 1H), 7.71 - 7.64 (m, 2H), 6.81 (d, J = 8.6 Hz, 1H), 5.07 (s, 2H), 4.95 (s, 2H), 4.39 - 4.33 (m, 2H), 3.84 - 3.66 (m, 4H), 3.61 - 3.53 (m, 3H), 3.39 (s, 3H), 1.29 - 1.23 (m, 6H) ppm 346 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.42 (s, 1H), 8.75 - 8.69 (m, 1H), 8.65 - 8.59 (m, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.48 - 8.45 (m, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.90 - 7.81 (m, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.(d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.83 (d, J = 6.0 Hz, 2H), 4.27 - 4.16 (m, 2H), 3.72 - 3.64 (m, 2H), 3.55 - 3.52 (m, 1H), 3.40 (brd, J = 2.4 Hz, 1H), 2.94 (s, 3H), 2.47 - 2.42 (m, 1H), 1.66- 1.55 (m, 1H), 1.51 -1.43 (m, 1H), 1.23-1.14 (m, 1H) ppm 347 577.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.69 - 9.58 (m, 1H), 9.39 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.46 - 8.39 (m, 1H), 8.30 - 8.19 (m, 1H), 7.(d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.30 - 7.20 (m, 1H), 7.19 - 7.08 (m, 2H), 4.97 (s, 2H), 4.81 (br d, J = 5.6 Hz, 2H), 4.28 - 4.14 (m, 2H), 3.76 - 3.62 (m, 2H), 3.55 - 3.48 (m, 5H), 3.31 - 3.30 (m, 2H), 3.23 (s, 3H), 2.86 (s, 3H) ppm 348 596.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.71 - 9.68 (m, 1H), 9.29 (s, 1H), 8.63 (s, 1H), 8.62 - 8.54 (m, 2H), 8.45 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.85 - 7.33 (m, 3H), 5.63 - 5.27 (m, 1H), 5.23 - 4.99 (m, 1H), 4.80 (d, J = 6.0 Hz, 2H), 3.38 (s, 3H), 2.86 - 2.70 (m, 4H) ppm 349 574.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.28 (s, 1H), 8.66 - 8.59 (m, 2H), 8.58 - 8.51 (m, 1H), 8.47 - 8.41 (m, 1H), 8.22 - 8.20 (m, 1H), 7.95 (s, 1H), 7.90 (d, J = 7.Hz, 1H), 7.74 - 7.67 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 5.- 5.02 (m, 2H), 4.92 (s, 2H), 4.37 - 4.30 (m, 2H), 4.00 - 3.97 (m, 2H), 3.72 - 3.69 (m, 2H), 3.55 - 3.51 (m, 2H), 3.35 (s, 3H), 2.71 - 2.64 (m, 1H), 1.00 - 0.91 (m, 2H), 0.- 0.70 (m, 2H) ppm 350 529.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.55-9.53 (m, 1H), 8.95 (s, 1H), 8.51 (d, J = 1.Hz, 1H), 8.29 (brs, 1H), 8.25-8.23 (m, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.Hz, 1H), 7.36 - 7.33 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.05 (s, 1H), 7.00 (d, J = 8.Hz, 1H), 4.97 (s, 2H), 4.69 (d, J = 6.0 Hz, 2H), 4.23-4.21 (m, 2H), 3.99-3.95 (m, 2H), 3.69 - 3.66 (m, 2H), 2.69- 2.66 (m, 2H), 2.27 (s, 3H), 1.92-1.86 (m,2H) ppm 351 628.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.60 (m, 1H), 9.41 (s, 1H), 8.71 - 8.60 (m, 2H), 8.43 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 8.13 (s, 1H), 7.91 (d, J = 7.Hz, 1H), 7.82 (s, 1H), 7.78 - 7.70 (m, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.32 (brs, 2H), 4.87 - 4.77 (m, 2H), 4.37 - 4.28 (m, 2H), 4.27 - 4.21 (m, 2H), 3.71 - 3.63 (m, 4H), 2.55 - 2.54 (m, 2H), 1.33 (s, 3H), 1.21 (d, J = 6.2 Hz, 6H), 0.88 (s, 4H) ppm 236 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 352 588.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.30 (s, 1H), 8.69 - 8.61 (m, 2H), 8.61 - 8.55 (m, 1H), 8.52 - 8.45 (m, 1H), 8.23 - 8.20 (m, 1H), 7.96 (s, 1H), 7.86 (d, J = 7.Hz, 1H), 7.73 - 7.67 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.(s, 2H), 4.93 (s, 2H), 4.50 - 4.43 (m, 1H), 4.38 - 4.30 (m, 3H), 3.56 - 3.51 (m, 2H), 3.42 (s, 3H), 3.14 - 3.03 (m, 2H), 2.80 - 2.77 (m, 1H), 2.26 - 2.15 (m, 1H), 1.77 - 1.64 (m, 1H), 1.53 - 1.39 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H) ppm 353 588.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.30 (s, 1H), 8.69 - 8.61 (m, 2H), 8.61 - 8.55 (m, 1H), 8.52 - 8.44 (m, 1H), 8.23 - 8.21 (m, 1H), 7.97 (s, 1H), 7.86 (d, J = 7.Hz, 1H), 7.73 - 7.67 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.(s, 2H), 4.93 (s, 2H), 4.50 - 4.43 (m, 1H), 4.38 - 4.31 (m, 3H), 3.56 - 3.51 (m, 2H), 3.42 (s, 3H), 3.14 - 3.03 (m, 2H), 2.80 - 2.76 (m, 1H), 2.26 - 2.15 (m, 1H), 1.77 - 1.65 (m, 1H), 1.53 - 1.39 (m, 1H), 1.08 (d, J = 6.8 Hz, 3H) ppm 354 588.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.49 - 9.46 (m, 1H), 9.39 (s, 1H), 8.72 - 8.56 (m, 2H), 8.29 (d, J = 2.1 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.- 7.68 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.79 (d, J = 5.6 Hz, 2H), 4.36-4.17 (m, 4H), 3.74 - 3.62 (m, 2H), 3.60 - 3.52 (m, 2H), 2.52 (br s, 2H), 2.35 - 2.26 (m, 5H), 1.21 (d,J = 6.2 Hz, 6H) ppm 355 624.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.89 - 9.67 (m, 1H), 9.41 (s, 1H), 8.80 - 8.59 (m, 3H), 8.53 (s, 1H), 8.46 (brs, 1H), 7.95- 7.89 (m, 1H), 7.87- 7.82 (m, 1H), 7.75- 7.73 (m, 1H), 7.65 - 7.36 (m, 1H), 7.04 (d, J = 8.6 Hz, 1H), 5.18 - 5.01 (m, 2H), 4.- 4.79 (m, 2H), 4.32 (br d, J = 11.4 Hz, 2H), 4.27 - 4.21 (m, 2H), 3.83 - 3.74 (m, 2H), 3.73 - 3.64 (m, 2H), 2.56 - 2.55 (m, 2H), 1.22 (d, J = 6.2 Hz, 6H) ppm 356 515.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.58 (m, 1H), 9.38 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.51 (d, J-1.6 Hz, 1H), 8.48- 8.45 (m, 1H), 8.23-8.21 (m, 1H), 8.(d, J = 9.2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J =7.8 Hz, 1H), 7.39 (d, J = 6.8 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.22 - 7.12 (m, 1H), 4.(s, 2H), 4.88 - 4.76 (m, 2H), 4.28 - 4.15 (m, 2H), 3.91 (s, 2H), 3.73 - 3.60 (m, 2H) ppm 357 566.3 1H NMR (400 MHz, CHLOROFORM-d) 6 = 9.52 - 9.25 (m, 1H), 8.62 (s, 1H), 8.48 - 8.22 (m, 4H), 8.18 (brs, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.50 (brd, J = 7.4 Hz, 1H), 7.33 (brd, J = 8.0 Hz, 1H), 6.93-6.58 (m, 1H), 5.14-5.00 (m, 4H), 4.44 - 4.35 (m, 2H), 3.96 - 3.89 (m, 1H), 3.46 - 3.38 (m, 2H), 0.95 - 0.87 (m, 2H), 0.83 (br s, 2H) ppm 358 598.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.60 (m, 1H), 9.38 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.53 - 8.51 (m, 2H), 8.26 - 8.24 (m, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.(s, 1H), 7.78 - 7.69 (m, 2H), 6.98 (d, J = 8.6 Hz, 1H), 6.47 - 6.15 (m, 1H), 4.97 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 4.10 - 4.08 (m, 2H), 3.84 - 3.(m, 2H), 3.71 - 3.64 (m, 2H), 3.59 - 3.57 (m, 2H), 3.27 (s, 3H) ppm 237 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 359 602.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.64 - 9.61 (m, 1H), 9.4Q (s, 1H), 8.71 - 8.58 (m, 2H), 8.51 (d, J = 1.6 Hz, 1H), 8.46 (d, J = 3.6 Hz, 1H), 8.28- 8.25 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.83 (s , 1H), 7.78 - 7.71 (m, 2H), 7.03 (d,J= 8.4 Hz, 1H), 5.02 - 4.90 (m, 2H), 4.82 (d, J = 3.6 Hz, 2H), 4.38 - 4.27 (m, 3H), 4.19 - 4.15 (m, 1H), 3.- 3.63 (m, 2H), 3.46 - 3.41 (m, 1H), 2.52 (s, 2H), 1.76 - 1.65 (m, 1H), 1.36 - 1.25 (m, 1H), 1.21 (d, J = 6.4 Hz, 6H), 0.97 - 0.94 (m, 3H) ppm 36Q 602.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.64 - 9.61 (m, 1H), 9.40 (s, 1H), 8.71 - 8.58 (m, 2H), 8.51 (d, J = 1.6 Hz, 1H), 8.42 (s, 1H), 8.28 - 8.25 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.78 - 7.68 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 5.05 - 4.91 (m, 2H), 4.81 (d, J = 4.8 Hz, 2H), 4.31 (d, J = 12.0 Hz, 3H), 4.19-4.15 (m, 1H), 3.74-3.(m, 2H), 3.46 - 3.41 (m, 1H), 2.48 - 2.42 (m, 2H), 1.81 - 1.64 (m, 1H), 1.35 - 1.(m, 1H), 1.21 (d, J = 6.4 Hz, 6H), 0.97 - 0.94 (m, 3H) ppm 361 574.5 1H NMR (400 MHz, METHANOL-d4) 6 = 9.30 (s, 1H), 8.70 - 8.65 (m, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H), 8.21 - 8.20 (m, 1H), 7.96 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.70 - 7.67 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 4.37 - 4.31 (m, 2H), 3.91 - 3.84 (m, 2H), 3.83 - 3.77 (m, 2H), 3.57 - 3.50 (m, 2H), 3.37 - 3.34 (m, 1H), 3.17 (s, 3H), 0.53 - 0.48 (m, 2H), 0.47 - 0.42 (m, 2H) ppm 362 572.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.58 - 9.56 (m, 1H), 9.40 (s, 1H), 8.71 - 8.58 (m, 2H), 8.46 (d, J = 1.6 Hz, 1H), 8.43 -8.39 (m, 1H), 8.14-8.12 (m, 1H), 7.94-7.(m, 1H), 7.79 (s, 1H), 7.77- 7.70 (m, 1H), 7.53 (d, J = 8.2 Hz, 1H),7.03 (d, J = 8.4 Hz, 1H), 4.80 (brd, J = 5.6 Hz, 2H), 4.31 (brd, J = 11.8 Hz, 2H), 3.74 - 3.58 (m, 3H), 3.16 - 3.07 (m, 2H), 2.65 - 2.57 (m, 2H), 2.31 - 2.11 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.2 Hz, 6H) ppm 363 572.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.56 (M, 1H), 9.39 (s, 1H), 8.73 - 8.58 (m, 2H), 8.45 (d, J = 1.6 Hz, 1H), 8.41 (brs, 1H), 8.14-8.12 (M, 1H), 7.91 (d, J = 7.Hz, 1H), 7.79 (s, 1H), 7.77 - 7.70 (m, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.Hz, 1H), 4.80 (br d, J = 5.6 Hz, 2H), 4.31 (br d, J = 11.6 Hz, 2H), 3.71 - 3.59 (m, 3H), 3.15 - 3.06 (m, 2H), 2.64 (brd, J = 4.0 Hz, 2H), 2.32 - 2.25 (m, 1H), 2.22 - 2.(m, 1H), 1.36 (d, J = 6.8 Hz, 3H), 1.21 (d,J=6.2 Hz, 6H) ppm 364 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.53 - 9.51 (m, 1H), 9.40 (s, 1H), 8.73 - 8.55 (m, 2H), 8.47 - 8.37 (m, 1H), 8.24 - 8.22 (m, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.82 (s, 1H), 7.78 - 7.71 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.81 (brd, J = 5.6 Hz, 2H), 4.31 (brd, J = 12.4 Hz, 2H), 3.82 - 3.74 (m, 1H), 3.72 - 3.64 (m, 2H), 3.59 - 3.57 (m, 1H), 3.05 - 2.95 (m, 1H), 2.48 - 2.44 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.2 Hz, 6H) ppm 238 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 365 560.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.59 (m, 1H), 9.40 (s, 1H), 8.74 - 8.58 (m, 2H), 8.49 - 8.42 (m, 1H), 8.40 (s, 1H), 8.37 - 8.31 (m, 1H), 8.06 - 8.04 (m, 1H), 7.(d, J = 7.4 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.78 - 7.69 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.83 (d, J = 5.8 Hz, 2H), 4.35 - 4.26 (m, 2H), 3.71 - 3.64 (m, 2H), 3.53 - 3.(m, 1H), 2.55-2.52 (m, 3H), 1.20-1.18 (m, 12H) ppm 366 584.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.63 - 9.61 (m, 1H), 9.40 (s, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.26 - 8.24 (m, 1H), 8.20 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.41 (s,1H), 7.31 (d, J = 8.0 Hz, 1H), 7.23 - 6.92 (m, 1H), 4.97 (s, 2H), 4.82 (br d, J = 5.Hz, 2H), 4.36 - 4.27 (m, 2H), 4.26 - 4.14 (m, 2H), 3.75 - 3.62 (m, 4H), 3.28 (s, 3H) ppm 367 518.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.67-9.51 (m, 1H), 9.11 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.36 (s, 1H), 8.31 (d, J = 2.0 Hz, 2H), 8.28 - 8.24 (m, 1H), 7.94 - 7.(m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.38-7.32 (m, 1H), 7.127.04 ־ (m, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.35 (s, 4H), 4.28 - 4.14 (m, 2H), 3.76 - 3.62 (m, 2H) ppm 368 554.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.73 - 9.53 (m, 1H), 9.39 (s, 1H), 8.62 - 8.46 (m, 2H), 8.36 - 8.20 (m, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.39 - 7.16 (m, 2H), 4.97 (s, 2H), 4.82 (d, J = 6.0 Hz, 2H), 4.34 - 4.12 (m, 2H), 3.92 (s, 3H), 3.76 - 3.58 (m, 2H), 2.08 (s, 3H) ppm 369 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.62 (m, 1H), 9.41 (s, 1H), 8.72 - 8.66 (m, 1H), 8.65 - 8.60 (m, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.39 - 8.31 (m, 1H), 8.27 - 8.25 (m, 1H), 7.89 - 7.80 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 6.0 Hz, 2H), 4.27 - 4.20 (m, 2H), 3.72 - 3.65 (m, 2H), 3.49- 3.47 (m, 1H), 3.36 - 3.36 (m, 1H), 3.27 (s, 3H), 2.20 - 2.10 (m, 1H), 1.- 1.75 (m, 1H), 1.31-1.30 (m, 1H), 1.05 - 0.96 (m, 1H) ppm 370 574.4 1H NMR (400 MHz, METHANOL־d4) 6 = 9.30 (s, 1H), 8.70 - 8.65 (m, 1H), 8.63 (d, J = 2.0 Hz, 1H), 8.60 - 8.57 (m, 1H), 8.23 - 8.21 (m, 1H), 7.96 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.70 - 7.63 (m, 2H), 6.79 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H), 4.95 - 4.(m, 2H), 4.84 - 4.80 (m, 2H), 4.64 - 4.61 (m, 2H), 4.36 - 4.33 (m, 2H), 4.05 (d, J = 7.2 Hz, 2H), 3.65 - 3.60 (m, 2H), 3.56 - 3.50 (m, 3H), 1.25 -1.18 (m, 3H) ppm 371 558.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.45 (s, 1H), 8.82 - 8.60 (m, 2H), 8.49 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.18-8.05 (m, 1H), 7.97- 7.79 (m, 3H), 7.75 - 7.73 (m, 1H), 7.04 (d, J = 8.6 Hz, 1H), 4.85 (brd,J= 5.6 Hz, 2H), 4.32 (br d, J = 12.0 Hz, 2H), 3.72 - 3.65 (m, 2H), 2.99 2.90 ־ (m, 1H), 2.54 (brs, 2H), 1.27 ־ 1.11 (m, 8H), 1.10 - 1.04 (m, 2H) ppm 239 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 372 576.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.61 (m, 1H), 9.38 (s, 1H), 8.67 (d, J = 8.6 Hz, 1H), 8.61 - 8.50 (m, 2H), 8.43 (brd, J = 3.4 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.82 - 7.77 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.70 - 7.62 (m, 1H), 6.78 (d, J = 8.Hz, 1H), 4.98 (s, 3H), 4.82 (d, J = 6.0 Hz, 2H), 4.23 - 4.21 m, 2H), 3.72 - 3.62 (m, 2H), 3.57 - 3.41 (m, 4H), 3.26 (s, 3H), 1.23-1.16 (m, 6H) ppm 373 612.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.68 - 9.56 (m, 1H), 9.39 (s, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.62 - 8.51 (m, 2H), 8.40 - 8.32 (m, 1H), 8.29 - 8.20 (m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.70 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.28 - 4.19 (m, 4H), 3.86 - 3.80 (m, 2H), 3.70 - 3.(m, 2H), 3.63 - 3.60 (m, 2H), 3.27 (s, 3H), 1.72 - 1.59 (m, 3H) ppm 374 588.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.30 (s, 1H), 8.69 - 8.65 (m, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.60-8.56 (m, 1H), 8.22-8.20 (m, 1H), 7.96 (s, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.70 - 7.61 (m, 2H), 6.79 (d, J = 8.6 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 4.56 - 4.46 (m, 1H), 4.37 - 4.31 (m, 2H), 3.92 - 3.84 (m, 2H), 3.62 - 3.60 (m, 2H), 3.56 - 3.50 (m, 2H), 3.39 (s, 3H), 2.46 - 2.35 (m, 2H), 2.30 - 2.16 (m, 2H), 1.85 - 1.76 (m, 2H) ppm 375 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.42 (s, 1H), 8.75 - 8.68 (m, 1H), 8.66 - 8.59 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.27 - 8.25 (m, 1H), 8.22 - 8.(m, 1H), 7.94 - 7.86 (m, 1H), 7.83 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.05 - 6.89 (m, 1H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.44 (d, J = 6.8 Hz, 2H), 4.24 - 4.21 (m, 2H), 3.72 - 3.64 (m, 2H), 2.88 - 2.73 (m, 1H), 2.15 - 2.05 (m, 2H), 1.96 - 1.84 (m, 4H) ppm 376 531.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.64 (m, 1H), 9.43 (s, 1H), 8.76 - 8.66 (m, 2H), 8.55 (d, J = 1.8 Hz, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.37 (brs, 1H), 8.28 - 8.(m, 1H), 7.95- 7.93 (m, 1H), 7.85 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.51 (d, J = 7.8 Hz, 1H), 4.99 (s, 2H), 4.84 (d, J = 5.8 Hz, 2H), 4.28 - 4.20 (m, 2H),4.17 - 4.15 (m, 1H), 4.02 - 4.00 (m, 1H), 3.93 - 3.84 (m, 2H), 3.75 - 3.65 (m, 3H),2.41 - 2.35 (m, 1H), 2.31 - 2.23 (m, 1H) ppm 377 557.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.64 (m, 1H), 9.42 (s, 1H), 8.74 - 8.63 (m, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 8.37 (d, J = 7.2 Hz, 1H), 8.27 (d, J = 7.Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.28 - 4.19 (m, 2H), 4.02 - 3.(m, 1H), 3.91 - 3.83 (m, 1H), 3.72 - 3.65 (m, 2H), 3.63 - 3.55 (m, 1H), 3.48 - 3.(m, 1H), 2.74-2.68 (m, 1H), 2.13-2.08 (m, 1H), 1.94- 1.85 (m, 1H), 1.45-1.(m, 1H), 1.10 (d, J = 4.0 Hz, 1H) ppm 240 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 378 557.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.64 (m, 1H), 9.42 (s, 1H), 8.74 - 8.63 (m, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.47 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 8.27 (d, J = 7.Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.28 - 4.19 (m, 2H), 4.02 - 3.(m, 1H), 3.91 - 3.83 (m, 1H), 3.72 - 3.65 (m, 2H), 3.63 - 3.55 (m, 1H), 3.48 - 3.(m, 1H), 2.74-2.68 (m, 1H), 2.13-2.08 (m, 1H), 1.94- 1.85 (m, 1H), 1.45-1.(m, 1H), 1.10 (d, J = 4.0 Hz, 1H) ppm 379 530.3 1H NMR (400 MHz, MeOD) 5 = 8.97 (s, 1H), 8.61 (d, J =2.0 Hz, 1H), 8.21-8.18 (m, 1H), 8.11 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.67-7.61 (m, 3H), 7.08-7.(m, 1H), 5.30-5.26 (m,1H), 5.04 (s, 2H), 4.85 - 4.83 (m, 2H), 4.34-4.32 (m, 2H), 3.53-3.51 (m, 2H), 2.98-2.93 (m, 1H), 2.86-2.85 (m, 1H), 2.16-2.14 (m, 1H), 1.90- 1.85 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H) ppm 380 519.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.50 - 9.48 (m, 1H), 8.93 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.36 (s, 1H), 8.26-8.14 (m, 3H), 7.71 (d, J = 8.0 Hz, 1H), 7.48-7.(m, 2H), 4.96 (s, 2H), 4.68 (d, J = 5.6 Hz, 2H), 4.26 - 4.16 (m, 2H), 4.00 - 3.90 (m, 2H), 3.71 (s, 3H), 3.68 - 3.64 (m, 2H), 2.77 - 2.75 (m, 2H), 1.99 (br d, J = 5.0 Hz, 2H) ppm 381 531.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.63 (m, 1H), 9.42 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.45 (s, 1H), 8.28 - 8.26 (m, 1H), 8.20 (d, J = 7.2 Hz, 1H), 7.92 - 7.88 (m, 1H), 7.83 (s, 1H), 7.75 (d, J =8.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 4.99 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.(d, J = 7.2 Hz, 2H), 4.27 - 4.20 (m, 2H), 3.73 - 3.64 (m, 2H), 1.38- 1.28 (m, 1H), 0.66 - 0.53 (m, 2H), 0.48 - 0.33 (m, 2H) ppm 382 56Q.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.64 - 9.62 (m, 1H), 9.38 (s, 1H), 8.70 - 8.63 (m, 1H), 8.60 - 8.56 (m, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.85 - 7.(m, 2H), 7.76 - 7.65 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.08 - 4.95 (m, 3H), 4.82 (d, J = 5.6 Hz, 2H), 4.58 - 4.43 (m, 2H), 4.26 - 4.19 (m, 2H), 4.01 - 3.85 (m, 2H), 3.72 - 3.65 (m, 2H), 3.19 (s, 3H), 2.65 - 2.60 (m, 2H) ppm 383 560.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.62 (m, 1H), 9.38 (s, 1H), 8.69 - 8.63 (m, 1H), 8.62 - 8.52 (m, 2H), 8.27 - 8.25 (m, 1H), 7.85 - 7.78 (m, 2H), 7.76 - 7.67 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.05- 5.02 (m, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.2 Hz, 2H), 4.56 - 4.43 (m, 2H), 4.26 - 4.20 (m, 2H), 4.00 - 3.86 (m, 2H), 3.71 - 3.65 (m, 2H), 3.19 (s, 3H), 2.65 - 2.60 (m, 2H) ppm 384 541.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.44 (s, 1H), 8.81 - 8.72 (m, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.48 - 8.41 (m, 2H), 8.31 - 7.89 (m, 3H), 7.86 (s, 1H), 7.76 - 7.70 (m, 1H), 7.27 (d, J = 8.2 Hz, 1H), 5.00 - 4.(m, 2H), 4.83 (br d, J = 5.2 Hz, 2H), 4.35 - 4.22 (m, 1H), 4.02 - 4.00 (m, 1H), 3.69 - 3.58 (m, 1H), 1.16 (d, J = 7.2 Hz, 3H) ppm 241 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 386 538.2 1H NMR (40Q MHz, DMSO-d6) 6 = 9.67 - 9.58 (m, 1H), 9.38 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 8.30 - 8.22 (m, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 1.6 Hz, 1H), 7.21 -7.12(m, 1H), 4.96 (s, 2H), 4.81 (br d, J = 5.6 Hz, 2H), 4.32 - 4.24 (m, 1H), 4.06 - 3.97 (m, 1H), 3.90 (s, 3H), 3.70 - 3.59 (m, 1H), 1.16 (d, J = 7.2 Hz, 3H) ppm 387 530.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.63 - 9.60 (m, 1H), 9.34 (s, 1H), 8.55 - 8.46 (m, 2H), 8.43 (s, 1H), 8.26 - 8.24 (m, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.82 - 7.67 (m, 3H), 6.90 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.29 - 4.17 (m, 2H), 3.87 (s, 3H), 3.71 - 3.62 (m, 2H), 2.05- 1.95 (m, 1H), 1.06- 0.97 (m, 2H), 0.86 - 0.75 (m, 2H) ppm 388 559.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.66 - 9.65 (m, 1H), 9.46 (s, 1H), 8.78 (d, J = 8.8 Hz, 1H), 8.62 (d, J = 7.6 Hz, 1H), 8.55 - 8.47 (m, 2H), 8.33 - 8.20 (m, 2H), 7.(s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.84 (d, J = 5.6 Hz, 2H), 4.31 -4.27 (m, 1H), 4.04 - 3.99 (m, 1H), 3.71 -3.59 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H) ppm 389 608.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.40 (s, 1H), 8.71 - 8.59 (m, 2H), 8.45 (d, J = 2.2 Hz, 2H), 8.40 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 7.4Hz, 1H), 7.(s, 1H), 7.77 - 7.71 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.38 - 4.26 (m, 4H), 3.73 - 3.62 (m, 4H), 2.52 (br s, 2H), 2.32 (br d,J=1.8 Hz, 2H), 1.(d, J = 6.4 Hz, 6H) ppm 39Q 581.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.74 - 9.59 (m, 1H), 9.42 (s, 1H), 8.76 - 8.69 (m, 1H), 8.68-8.60 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.40-8.34 (m, 1H), 8.31 - 8.(m, 2H), 7.97- 7.87 (m, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.Hz, 1H), 4.98 (s, 2H), 4.83 (br d, J = 5.6 Hz, 2H), 4.54 (d, J = 6.4 Hz, 2H), 4.27 - 4.18 (m, 2H), 3.77 - 3.60 (m, 2H), 2.85 - 2.68 (m, 3H), 2.60 - 2.54 (m, 2H) ppm 391 567.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.42 (s, 1H), 8.76 - 8.68 (m, 1H), 8.67 - 8.60 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.30 - 8.21 (m, 2H), 7.95 - 7.(m, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.74 - 4.59 (m, 1H), 4.44 - 4.39 (m, 1H), 4.29 - 4.18 (m, 2H), 3.75 - 3.64 (m, 2H), 2.41 - 2.33 (m, 1H), 1.78 -1.71 (m, 1H), 1.65 - 1.49 (m, 1H) ppm 392 551.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.64 - 9.61 (m, 1H), 9.43 (s, 1H), 8.74 - 8.65 (m, 2H), 8.55 - 8.48 (m, 2H), 8.28 - 8.26 (m, 1H), 7.99 - 7.97 (m, 1H), 7.86 (s, 1H), 7.(d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.83 (br d, J = 5.6 Hz, 2H), 4.29 - 4.27 (m, 1H), 4.02 - 3.99 (m, 1H), 3.68 - 3.62 (m, 1H), 2.52 (brs, 2H), 2.14-2.06 (m, 1H), 1.17 (d, J = 7.2 Hz, 3H) ppm 242 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 393 551.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.61 (m, 1H), 9.43 (s, 1H), 8.74 - 8.65 (m, 2H), 8.55 - 8.48 (m, 2H), 8.28 - 8.26 (m, 1H), 7.99 - 7.97 (m, 1H), 7.86 (s, 1H), 7.(d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.83 (brd, J = 5.6 Hz, 2H), 4.29 - 4.26 (m, 1H), 4.02 - 4.00 (m, 1H), 3.68 - 3.62 (m, 1H), 2.52 (br s, 2H), 2.14 - 2.05 (m, 1H), 1.17 (d, J = 7.2 Hz, 3H) ppm 394 556.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.57 - 9.55 (m, 1H), 9.03 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.25-8.24 (m, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.26 (d, J = 2.4 Hz, 1H), 4.98 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 2H), 4.15 - 4.05 (m, 2H), 3.74 - 3.63 (m, 2H), 2.79 - 2.76 (m, 2H), 1.97 - 1.87 (m, 3H), 0.98 - 0.92 (m, 2H), 0.73 - 0.68 (m, 2H) ppm 395 548.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.65 - 9.62 (m, 1H), 9.03 (s, 1H), 8.40 (d, J =1.2 Hz, 1H), 8.35 - 8.30 (m, 1H), 8.20 - 8.11 (m, 2H), 7.98 (d, J 1.6 Hz, 1H), 7.(d, J = 9.2 Hz, 1H), 7.52 - 7.42 (m, 2H), 5.02 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 4.17 - 4.09 (m, 2H), 3.80 - 3.72 (m, 2H), 2.80 - 2.77 (m, 2H), 2.25 (s, 3H), 1.97-1.91 (m, 2H) ppm 396 544.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.54 (m, 1H), 9.03 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.55 - 7.39 (m, 2H), 4.96 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.30 - 4.27 (m, 1H), 4.17 - 4.09 (m, 2H), 4.04 - 4.(m, 1H), 3.70 - 3.60 (m, 1H), 2.80 - 2.79 (m, 2H), 2.24 (s, 3H), 1.97 - 1.92 (m, 2H), 1.16 (d. J = 7.2 Hz, 3H) ppm 397 564.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.62 (m, 1H), 9.48 (s, 1H), 8.78 (d, J = 8.8 Hz, 1H), 8.63 (d, J = 5.0 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.26 - 8.24 (m, 1H), 8.02 - 7.91 (m, 2H), 7.74 (d, J = 7.8 Hz, 1H),7.67 - 7.32 (m, 2H), 4.98 (s, 2H), 4.86 (br d, J = 6.0 Hz, 2H), 4.27 - 4.20 (m, 2H),3.98 (s, 3H), 3.71 - 3.65 (m, 2H) ppm 398 600.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.38 (s, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.59 - 8.52 (m, 2H), 8.28 - 8.26 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.(s, 1H), 7.78 - 7.70 (m, 2H), 7.16 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 6.Hz, 2H), 4.62 - 4.49 (m, 1H), 4.28 - 4.19 (m, 2H), 3.99 - 3.97 (m, 2H), 3.73 - 3.(m, 2H), 3.54 - 3.48 (m, 2H), 2.27 - 2.10 (m, 3H), 1.81 (d, J =10.8 Hz, 2H), 1.03 - 0.94 (m, 2H), 0.70 - 0.58 (m, 2H) ppm 399 541.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.64 (m, 1H), 9.45 (s, 1H), 8.81 - 8.73 (m, 1H), 8.72 - 8.66 (m, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.28 - 8.26 (m, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.45 - 6.85 (m, 1H), 4.99 (s, 2H), 4.84 (d, J = 5.2 Hz, 2H), 4.30-4.19 (m, 2H), 4.14 (s, 3H), 3.75 - 3.63 (m, 2H) ppm 243 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 400 563.3 1H NMR (400 MHz, METHANOL-d4) 6 = 8.88 (brs, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.31 (s, 1H), 8.24 -8.13 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.43 (d, J = 9.4 Hz, 1H), 5.04 (s, 2H), 4.81 (s, 2H), 4.38 - 4.31 (m, 2H), 4.22 - 4.20 (m, 2H), 4.- 3.96 (m, 2H), 3.72 - 3.70 (m, 2H), 3.57 - 3.49 (m, 2H), 3.29 (s, 3H), 2.88 - 2.86 (m, 2H), 2.17-2.08 (m, 2H) ppm 401 562.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.64 - 9.62 (m, 1H), 9.46 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.24 - 8.22 (m, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.62 - 7.60 (m, 1H), 6.85 - 6.83 (m, 1H), 6.- 6.34 (m, 1H), 4.97 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.25 - 4.19 (m, 2H), 3.74 - 3.65 (m, 6H), 3.12 - 3.08 (m, 4H) ppm 402 593.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.59 (m, 1H), 9.35 (s, 1H), 8.57 - 8.49 (m, 2H), 8.47 (s, 1H), 8.24 - 8.22 (m, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.26 - 7.24 (m, 1H), 6.85 - 6.83 (m, 1H), 4.97 (s, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.- 4.18 (m, 4H), 3.70 - 3.63 (m, 2H), 3.58 - 3.56 (m, 2H), 3.37 (br s, 2H), 3.27 (s, 5H) ppm 404 559.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.71- 9.68 (m, 1H), 9.43 (s, 1H), 8.65 (d, J = 8.Hz, 1H), 8.48 - 8.38 (m, 2H), 8.24 - 8.13 (m, 2H), 7.84 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.14 - 6.83 (m, 1H), 5.02 (s, 2H), 4.82 (br d, J = 5.6 Hz, 2H), 4.27 - 4.20 (m, 2H), 4.02 (s, 3H), 3.79 - 3.73 (m, 2H) ppm 405 555.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.62 (m, 1H), 9.43 (s, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.48 - 8.43 (m, 1H), 8.27 - 8.25 (m, 1H), 8.(d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.48 (d, J =7.8 Hz, 1H), 7.17 - 6.80 (m, 1H), 4.96 (s, 2H), 4.87 - 4.77 (m, 2H), 4.35 - 4.20 (m, 1H), 4.06 - 3.96 (m, 4H), 3.70 - 3.57 (m, 1H), 1.20-1.13 (m, 3H) ppm 406 567.3 1H NMR (400 MHz, DMSO-d6) 6 9.82 (t, J = 5.8 Hz, 1H), 8.98 (dd, J = 9.0, 1.0 Hz, 1H), 8.89 (d, J = 9.0 Hz, 1H), 8.61 (d, J = 2.2 Hz, 1H), 8.30 (dd, J = 8.4, 2.2 Hz, 1H), 8.19 (d, J = 1.0 Hz, 1H), 7.96-7.91 (m, 2H), 7.79 (dd, J = 8.5, 7.4 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.13 (d, J = 5.7 Hz, 2H), 4.33 (dd, 2H), 3.74-3.62 (m, 2H), 3.42 (s, 3H), 2.55 (m, 2H), 1.22 (d, J = 6.2 Hz, 6H). 407 609.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.93-9.90 (m, 1H), 9.42-9.40 (m, 2H), 8.97 (d, J = 1.6 Hz, 1H), 8.68-8.61 (m, 2H), 8.44 (s, 1H), 7.91-7.88 (m, 2H), 7.77-7.73 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.86 (br d, J = 6.0 Hz, 2H), 4.32 (brd, J = 12.4 Hz, 2H), 3.74-3.72 (m, 2H), 3.70 - 3.66 (m, 2H), 2.54 - 2.52 (m, 4H), 2.30 (br d, J = 3.Hz, 2H), 1.22 (d, J = 6.42 Hz, 6H) ppm 244 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 408 530.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.62-9.47 (m, 1H), 8.91 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.41 (brs, 1H), 8.31 -8.22 8.18 (d, J = 9.2 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.30 (s, 1H), 7.(d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.89 (s, 2H), 4.67 (d, J = 5.6 Hz, 2H), 4.31 - 4.(m, 2H), 4.10 - 3.99 (m, 2H), 3.74 - 3.64 (m, 2H), 2.92 - 2.83 (m, 2H), 2.43 (s, 3H) ppm 409 588.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.60 (m, 1H), 9.37 (s, 1H), 8.58 - 8.48 (m, 2H), 8.26 - 8.24 (m, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.74 - 7.70 (m, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.06-7.02 (m, 1H), 4.97 (s, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.64-4.53 (m, 1H), 4.37-4.18 (m, 4H), 3.98-3.83 (m, 1H), 3.71 -3.63 (m, 2H), 3.53- 3.40 (m, 1H), 3.22 - 3.15 (m, 1H), 2.81 -2.72 (m, 1H), 2.64 - 2.58 (m, 1H), 2.18 - 2.01 (m, 2H) ppm 410 588.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.37 (s, 1H), 8.58 - 8.47 (m, 2H), 8.26 - 8.24 (m, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.74 - 7.70 (m, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.06 - 7.02 (m, 1H), 4.97 (s, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.64-4.53 (m, 1H), 4.37 - 4.17 (m, 4H), 3.98 - 3.83 (m, 1H), 3.71 - 3.63 (m, 2H), 3.53-3.40 (m, 1H), 3.22 - 3.14 (m, 1H), 2.81 -2.72 (m, 1H), 2.64 - 2.58 (m, 1H), 2.18 - 2.01 (m, 2H) ppm 411 519.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.60 (m, 1H), 9.37 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.30 - 8.23 (m, 2H), 8.19 (d, J = 8.4 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.96 (s, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.30 - 4.26 (m, 1H), 4.05 - 3.95 (m, 4H), 3.68 - 3.61 (m, 1H), 2.(s, 3H), 1.16 (d, J = 7.2 Hz, 3H) ppm 412 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.63 (m, 1H), 9.39 (s, 1H), 8.66 (s, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.28 - 8.25 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.77 - 7.71 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 3.73 - 3.64 (m, 2H), 3.39 - 3.34 (m, 1H), 3.23 (s, 3H), 3.19-3.13 (m, 4H), 2.74-2.72 (m, 1H), 1.50- 1.48 (m, 1H), 1.23-1.10 (m, 1H), 0.65-0.62 (m, 1H) ppm 413 574.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.63 (m, 1H), 9.39 (s, 1H), 8.65 (s, 2H), 8.54 (d,J=1.6 Hz, 1H), 8.33 (s, 1H), 8.28 - 8.26 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.77 - 7.71 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 3.73 - 3.65 (m, 2H), 3.39 - 3.34 (m, 1H), 3.23 (s, 3H), 3.19-3.13 (m, 4H), 2.74-2.73 (m, 1H), 1.50- 1.48 (m, 1H), 1.23-1.10 (m, 1H), 0.65-0.62 (m, 1H) ppm 245 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 414 544.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.60 (m, 1H), 9.35 (s, 1H), 8.64-8.62 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.31 (brs, 1H), 8.27-8.25 (m, 1H), 7.77 (s, 1H), 7.74- 7.72 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.24- 4.21 (m, 2H), 3.69-3.64 (m, 3H), 3.19(8, 3H), 2.84-2.74 (m, 2H), 1.87-1.78 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H) ppm 415 587.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.39 (s, 1H), 9.32 (m, 1H), 8.70 - 8.60 (m, 2H), 8.47 (d, J = 2.0 Hz, 1H), 8.10 (m, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.18 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.78 (brd, J = 5.6 Hz, 2H), 4.(br d, J = 11.6 Hz, 2H), 3.73 - 3.63 (m, 2H), 3.52 - 3.43 (m, 4H), 3.08 (s, 3H), 2.55 - 2.53 (m, 2H), 2.17 - 2.07 (m, 2H), 1.22 (d, J = 6.1 Hz, 6H) ppm 416 588.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.59- 9.52 (m, 1H), 9.39 (s, 1H), 8.71 - 8.58 (m, 2H), 8.46 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.27 - 8.24 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.70 (s, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.80 (d, J = 5.Hz, 2H), 4.31 (d, J 11.2 Hz, 2H), 4.25 - 4.14 (m, 1H), 3.69 - 3.65 (m, 2H), 3.64 - 3.58 (m, 2H), 2.32 - 2.05 (m, 4H), 1.43 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 417 533.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.61 (m, 1H), 9.41 (s, 1H), 8.73 - 8.58 (m, 2H), 8.54 (s, 1H), 8.33 - 8.24 (m, 1H), 8.06 (s, 1H), 7.84 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 5.02 - 4.93 (m, 2H), 4.87 - 4.75 (m, 2H), 4.49 - 4.47 (m, 2H), 4.- 4.24 (m, 1H), 4.06 - 3.95 (m, 1H), 3.71 - 3.61 (m, 1H), 2.39 (s, 3H), 1.39 - 1.37 (m, 3H), 1.17 (d, J = 7.0 Hz, 3H) ppm 418 588.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.63 - 9.51 (m, 1H), 9.39 (s, 1H), 8.72 - 8.58 (m, 2H), 8.46 (d, J = 2.4 Hz, 1H), 8.33 - 8.19 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.81 - 7.67 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.80 (d, J = 6.0 Hz, 2H), 4.31 (br d, J = 11.2 Hz, 2H), 4.23 -4.13 (m, 1H), 3.71 - 3.59 (m, 4H), 2.34 - 2.11 (m, 4H), 1.43 (d, J = 6.0 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 419 554.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.73 - 9.53 (m, 1H), 9.39 (s, 1H), 8.62 - 8.46 (m, 2H), 8.36 - 8.20 (m, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.39 - 7.16 (m, 2H), 4.97 (s, 2H), 4.82 (d, J = 6.0 Hz, 2H), 4.34 - 4.12 (m, 2H), 3.92 (s, 3H), 3.76 - 3.58 (m, 2H), 2.08 (s, 3H) ppm 420 531.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 - 9.54 (m, 1H), 9.02 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.45 (brs, 1H), 8.28 - 8.21 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 6.79 (s, 1H), 6.76 -6.70 (m, 1H), 4.98 (s, 2H), 4.71 (d, J = 6.0 Hz, 2H), 4.28 - 4.20 (m, 6H), 3.71 - 3.66 (m, 2H), 2.26 (s, 3H) ppm 246 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 421 557.3 1H NMR (400 MHz, DMSO-d6) 6 9.63 (t, J = 5.9 Hz, 1H), 9.38 (s, 1H), 8.62 (d, J = 8.6 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.24 (dd, J = 7.8, 1.9 Hz, 1H), 8.01 (d, J = 8.Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.26 - 7.14 (m, 2H), 6.70 (dd, J = 7.4, 1.3 Hz, 1H), 4.97 (s, 2H), 4.81 (d, J = 5.8 Hz, 2H), 4.26 - 4.15 (m, 2H), 3.(dt, J = 11.3, 3.2 Hz, 2H), 3.72 - 3.62 (m, 2H), 3.62 - 3.55 (m, 2H), 3.45 (id, J = 11.5, 2.7 Hz, 1H), 3.30 (d, J = 7.0 Hz, 2H), 3.04 (td, J = 12.3, 3.5 Hz, 1H), 2.84 (dd, J = 16.4, 7.4 Hz, 1H). 422 52Q.25 1H NMR (400 MHz, DMSO-d6) 6 9.85 (t, J = 5.8 Hz, 1H), 9.00 (d, J = 9.0 Hz, 1H), 8.88 (d, J = 9.0 Hz, 1H), 8.42-8.34 (m, 2H), 8.24 (s, 1H), 8.17 (dd, J = 10.1, 1.7 Hz, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 5.14 (d, J = 5.6 Hz, 2H), 5.(s, 2H), 4.23 (dd, J = 6.3, 3.5 Hz, 2H), 3.76 (dd, J = 5.9, 3.6 Hz, 2H), 2.31-2.21 (m, 1H), 1.18-1.02 (m, 4H). 423 516.25 1H NMR (400 MHz, DMSO-d6) 6 9.78 (t, J = 5.8 Hz, 1H), 9.00 (dd, J = 9.0, 1.0 Hz, 1H), 8.87 (d, J = 9.0 Hz, 1H), 8.52 (d, J = 1.9 Hz, 1H), 8.37 (dd, J = 7.8, 1.0 Hz, 1H), 8.27 (dd, J = 7.8, 1.9 Hz, 1H), 8.22 (d, J = 1.0 Hz, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.53 (dd, J = 7.9, 1.0 Hz, 1H), 5.14 (d, J = 5.7 Hz, 2H), 4.96 (s, 2H), 4.29 (dd, J = 13.2, 2.4 Hz, 1H), 4.02 (dd, J = 13.3, 5.8 Hz, 1H), 3.73- 3.58 (m, 1H), 2.30-2.21 (m, 1H), 1.23-0.99 (m, 7H). 424 520.2 1H NMR (300 MHz, DMSO-d6) 6 9.99 (s, 1H), 9.84 (t, J = 5.8 Hz, 1H), 9.59 (s, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.37 (dd, J = 7.8, 1.0 Hz, 1H), 8.26 (dd, J = 10.1, 1.7 Hz, 1H), 8.07-7.93 (m, 2H), 7.62 (dd, J = 7.9, 1.0 Hz, 1H), 5.10 (s, 2H), 4.94 (d, J = 5.7 Hz, 2H), 4.30 (dd, J = 6.4, 3.5 Hz, 2H), 3.84 (t, J = 4.8 Hz, 2H), 2.38 - 2.31 (m, 1H), 1.27- 1.09 (m, 4H). 425 570.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.62 (m, 1H), 9.35 (s, 1H), 8.74 (d, J = 8.Hz, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.28-8.25 (m, 1H), 8.(s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.24-4.22 (m, 2H), 3.76-3.(m, 1H), 3.86-2.69 (m, 2H), 2.91 - 2.82 (m, 1H), 2.76 - 2.69 (m, 2H), 1.78-1.75 (m, 2H), 1.19-1.13 (m, 6H), 0.78-0.77 (m, 1H), 0.67-0.59 (m, 2H) ppm 426 546.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.60 (m, 1H), 9.33 (s, 1H), 8.65 - 8.50 (m, 3H), 8.46 (s, 1H), 8.26 - 8.24 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.10 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.32 - 4.21 (m, 2H), 4.20 - 4.08 (m, 2H), 3.78 - 3.62 (m, 3H), 3.18 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H) ppm 427 553.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.65 - 9.63 (m, 1H), 9.42 (s, 1H), 8.79 - 8.72 (m, 1H), 8.69 - 8.63 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.49 - 8.39 (m, 1H), 8.33 (d, J = 7.4 Hz, 1H), 8.27 - 8.24 (m, 1H), 8.00 - 7.98 (m, 1H), 7.85 (s, 1H),7.74 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H), 4.94 - 4.86 (m, 1H), 4.83 (brd, J = 5.6 Hz, 2H), 4.28 - 4.18 (m, 2H), 3.72 - 3.62 (m, 2H), 2.21 - 2.15 (m, 1H), 1.94 - 1.87 (m, 1H) ppm 247 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 428 586.5 1H NMR (400 MHz, CHLOROFORM-d) 6 = 9.25 (s, 1H), 8.62 - 8.53 (m, 2H), 8.(d, J = 8.8 Hz, 1H), 8.20 -8.18 (m, 1H), 8.04 - 7.98 (m, 2H), 7.83 - 7.76 (m, 1H),7.69 - 7.67 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H),5.06 - 5.02 (m, 2H), 5.01 - 4.96 (m, 2H), 4.81 - 4.79 (m, 2H), 4.65 - 4.63 (m, 2H),4.41 - 4.36 (m, 2H), 4.19 (d, J = 7.2 Hz, 2H), 3.44 - 3.40 (m, 3H), 2.54 - 2.46 (m,1H), 0.98 (brd, J = 5.2 Hz, 2H), 0.75 - 0.73 (m, 2H) ppm 429 544.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 - 9.54 (m, 1H), 9.02 (s, 1H), 8.54 (d, J = 1.4 Hz, 1H), 8.28 - 8.21 (m, 1H), 8.12 (d, J = 9.4 Hz, 1H), 7.93 (s, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 4.98 (s, 2H), 4.73 (brd, J = 5.Hz, 2H), 4.28 - 4.19 (m, 2H), 4.16 - 4.09 (m, 2H), 3.74 - 3.65 (m, 2H), 2.76 - 2.(m, 2H), 2.23 - 2.20 (m, 3H), 2.20 - 2.15 (m, 3H), 1.99 - 1.91 (m, 2H) ppm 430 530.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.63 - 9.61 (m, 1H), 9.40 (s, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.52 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.17-7.15 (m, 1H), 7.01 (d, J = 6.4 Hz, 1H), 4.96 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.21 - 4.20 (m, 2H), 3.68 - 3.67 (m, 2H), 3.50 (s, 3H), 2.23 - 2.20 (m, 1H), 1.02 - 1.00 (m, 2H), 0.75 - 0.73 (m, 2H) ppm 431 622.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.73 - 9.71 (m, 1H), 9.40 (s, 1H), 8.65 - 8.63 (m, 2H), 8.51 (d, J = 1.6 Hz, 2H), 8.43 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.(s, 1H), 7.78 - 7.72 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.28 -5.11 (m, 2H), 4.82 (br d, J = 5.4 Hz, 2H), 4.34 - 4.28 (m, 3H), 4.02 - 4.00 (m, 1H), 3.80 - 3.72 (m, 1H), 3.71 - 3.64 (m, 2H), 2.54 - 2.52 (m, 2H), 1.22 (d, J = 6.2 Hz, 6H), 1.18 (d, J = 7.0 Hz, 3H) ppm 432 622.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.73 - 9.70 (m, 1H), 9.40 (s, 1H), 8.65 - 8.64 (m, 2H), 8.50 (d, J = 1.6 Hz, 2H), 8.43 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.(s, 1H), 7.78 - 7.72 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.28 - 5.12 (m, 2H), 4.81 (brd, J = 5.4 Hz, 2H), 4.34 - 4.28 (m, 3H), 4.02 - 4.00 (m, 1H), 3.80 - 3.72 (m, 1H), 3.71 - 3.64 (m, 2H), 2.54 - 2.52 (m, 2H), 1.22 (d, J = 6.2 Hz, 6H), 1.18 (d, J = 7.0 Hz, 3H) ppm 433 614.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.55 - 9.52 (m, 1H), 9.38 (s, 1H), 8.68 - 8.58 (m, 2H), 8.44 (d, J = 2.2 Hz, 1H), 8.31 (s, 1H), 8.25 - 8.23 (m, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.79 (br d, J = 5.6 Hz, 2H), 4.30 (br d, J = 11.2 Hz, 2H), 3.71 - 3.60 (m, 3H), 3.60 - 3.50 (m, 1H), 3.49 - 3.41 (m, 1H), 2.46 (brs, 5H), 1.22-1.19 (m, 6H), 0.65 - 0.47 (m, 3H), 0.43 - 0.32 (m, 1H) ppm 248 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 434 537.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.96-9.93 (m, 1H), 9.46 (d, J = 5.2 Hz, 2H), 9.(d, J = 1.6 Hz, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.79 (s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.49 - 8.46 (m, 1H), 7.95 (s, 1H), 4.88 (br d, J = 5.6 Hz, 2H), 3.75-3.72 (m, 2H), 2.55 - 2.54 (m, 2H), 2.35-2.28 (m, 3H), 1.16 -1.14 (m, 4H) ppm 435 614.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57-9.56 (m, 1H), 9.39 (s, 1H), 8.67-8.60 (m, 2H), 8.45 (d, J = 2.4 Hz, 1H), 8.27-8.24 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.77-7.(m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.80 (brd, J = 5.6 Hz, 2H), 4.32 (br d, J = 11.6 Hz, 2H), 3.69-3.63 (m, 3H), 3.61 - 3.52 (m, 1H), 3.48-3.(m, 1H), 2.52 (brs, 2H), 2.46-2.29 (m, 3H), 1.21 (d, J = 6.0 Hz, 6H), 0.62-0.57 (m, 2H), 0.50-0.37 (m, 2H) ppm 436 588.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 (s, 1H), 9.39 (s, 1H), 8.71 - 8.59 (m, 2H), 8.54 (d. J = 1.6 Hz, 1H), 8.36 - 8.34 (m, 1H), 8.27 - 8.25 (m, 1H), 7.87 - 7.66 (m, 4H), 6.81 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.79 - 4.70 (m, 1H), 4.26 - 4.20 (m, 2H), 3.71 - 3.65 (m, 2H), 3.37 - 3.36 (m, 2H), 3.27 (s, 3H), 3.(s, 3H), 2.40 - 2.30 (m, 3H), 2.01 - 1.90 (m, 2H) ppm 437 588.4 1H NMR (400 MHz, DMSO-d6) 0 = 9.64 - 9.61 (m, 1H), 9.39 (s, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.54 (s, 1H), 8.26 - 8.25 (m, 1H), 7.83 - 7.(m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.68 - 7.66 (m, 1 H), 7.02 (d, J = 8.4 Hz, 1H), 4.(s, 2H), 4.81 (d, J = 6 Hz, 2H), 4.24 - 4.20 (m, 2H), 3.71 - 3.65 (m, 5H), 3.43 - 3.(m, 5H), 2.11 -2.01 (m, 1 H), 2.00- 1.98 (m, 1H),1.89 - 1.86 (m, 2H), 1.64-1.(m, 2 H), 0.94 (d, J = 6.8 Hz, 1H) ppm 438 588.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.60 (m, 1H), 9.39 (s, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.58 (d, J = 8.8 Hz, 1H), 8.54 (s, 1H), 8.26 - 8.25 (m, 1H), 7.83 - 7.(m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.68 - 7.65 (m, 1 H), 7.02 (d, J = 8.4 Hz, 1H), 4.(s, 2H), 4.81 (d, J = 6 Hz, 2H), 4.24 - 4.20 (m, 2H), 3.71 - 3.65 (m, 5H), 3.43 - 3.(m, 5H), 2.11 -2.01 (m, 1 H), 2.00- 1.98 (m, 1H),1.89 - 1.86 (m, 2H), 1.64-1.(m, 2 H), 0.94 (d, J = 6.8 Hz, 1H) ppm 439 546.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 - 9.54 (m, 1H), 9.07 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.28-8.21 (m, 1H), 8.20 - 8.12 (m, 1H),8.08(d,J-5.8Hz, 1H), 7.(d, J = 9.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 6.83 (d, J = 5.8 Hz, 1H), 4.97 (s, 2H), 4.73 (brd, J = 5.6 Hz, 2H), 4.22 - 4.20 (m, 2H), 4.13 - 4.10 (m, 2H), 3.92 - 3.83 (m, 3H), 3.71 - 3.63 (m, 2H), 2.71 - 2.62 (m, 2H), 1.97 - 1.87 (m, 2H) ppm 249 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 440 531.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.57 (m, 1H), 9.09 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.27 - 8.20 (m, 2H), 8.02 (s 5 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 4.97 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.26-4.15 (m, 4H), 3.72 - 3.65 (m, 2H), 2.97 - 2.93 (m, 2H), 2.41 (s, 3H), 2.09 - 2.00 (m, 2H) ppm 441 559.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.70 - 9.56 (m, 1H), 9.10 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.32-8.22 (m, 1H), 8.19-8.11 (m, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.80 - 7.69 (m, 2H), 7.56 (s, 1H), 7.13 (brs, 1H), 4.98 (s, 2H), 4.76 (brd, J = 5.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 4.17 - 4.07 (m, 2H), 3.74 - 3.63 (m, 3H), 2.92 (s, 6H), 2.82 - 2.74 (m, 2H), 2.00 - 1.87 (m, 2H) ppm 442 531.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.64 - 9.51 (m, 1H), 9.04 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.30 (brs, 1H), 8.27 -8.23 (m, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz. 1H), 7.63 - 7.54 (m, 1H), 7.46 (s, 1H), 7.12 - 6.(m, 2H), 4.98 (s, 2H), 4.72 (brd, J = 5.6 Hz, 2H), 4.32 - 4.16 (m, 4H), 3.72 - 3.(m, 2H), 3.40 - 3.38 (m, 2H), 2.93 (s, 3H) ppm 443 516.2 1H NMR (300 MHz, DMSO-d6) 6 9.92 (s, 1H), 9.67 (t, J = 5.8 Hz, 1H), 9.52 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.29 (ddd, J = 9.6, 7.8, 1.4 Hz, 2H), 7.96 - 7.86 (m, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 7.8, 1.0 Hz, 1H), 4.97 (s, 2H), 4.86 (d, J = 5.Hz, 2H), 4.29 (dd, J = 13.2, 2.4 Hz, 1H), 4.02 (dd, J = 13.3, 5.9 Hz, 1H), 3.65 (t, J = 7.5 Hz, 1H), 2.28-2.26 (m, 1H), 1.21 - 1.12 (m, 5H), 1.11 -1.02 (m, 2H). 444 602.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57- 9.56 (m, 1H), 9.40 (s, 1H), 8.71 - 8.59 (m, 2H), 8.47 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.(s, 1H), 7.77 - 7.68 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 4.(d, J = 12.4 Hz, 2H), 3.73 - 3.62 (m, 3H), 3.47 - 3.38 (m, 4H), 3.25 (s, 3H), 2.53 - 2.52 (m, 2H), 2.31 - 2.23 (m, 2H), 1.21 (d, J = 6.4 Hz, 6H) ppm 445 560.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.57 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 9.6 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.05 (d, J = 7.Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.2 Hz, 2H), 4.36 (s, 2H), 4.26 - 4.19 (m, 2H), 4.17 - 4.10 (m, 2H), 3.73 - 3.65 (m, 2H), 3.34 (s, 3H), 2.82 - 2.79 (m, 2H), 2.02 - 1.89 (m, 2H) ppm 446 602.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.56 - 9.54 (m, 1H), 9.40 (s, 1H), 8.69 - 8.61 (m, 2H), 8.47 (d, J = 2.0 Hz, 1H), 8.19 - 8.17 (m, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.80 (s, 1H), 7.78 - 7.67 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.87 - 4.74 (m,2H), 4.37 - 4.27 (m, 2H), 3.74 - 3.62 (m, 3H), 3.46 - 3.40 (m, 4H), 3.25 (s, 3H), 2.(br s, 2H), 2.30 - 2.23 (m, 2H), 1.21 (d, J = 6.2 Hz, 6H) ppm 250 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 447 560.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.57 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.(s, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.37 (s, 2H), 4.27-4.19 (m, 2H), 4.- 4.09 (m, 2H), 3.73 - 3.63 (m, 2H), 3.30 (s, 3H), 2.85 - 2.81 (m, 2H), 1.99 - 1.93 (m, 2H) ppm 448 572.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.46 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.27 - 8.24 (m, 1H), 7.92 (s, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 3.6 Hz, 1H), 4.98 (s, 2H), 4.85 (d, J = 6.Hz, 2H), 4.36 (d, J = 6.0 Hz, 2H), 4.28 - 4.16 (m, 2H), 3.81 - 3.76 (m, 1H), 3.72 - 3.64 (m, 2H), 3.21 (s, 3H), 1.07 (d, J = 6.0 Hz, 3H) ppm 449 572.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.46 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.44 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.27 - 8.24 (m, 1H), 7.92 (s, 1H), 7.81 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 3.2 Hz, 1H), 4.98 (s, 2H), 4.85 (d, J = 5.Hz, 2H), 4.36 (d, J = 5.6 Hz, 2H), 4.26 - 4.19 (m, 2H), 3.83 - 3.76 (m, 1H), 3.71 - 3.64 (m, 2H), 3.20 (s, 3H), 1.07 (d, J = 6.0 Hz, 3H) ppm 450 515.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.76-9.74 (m, 1H), 9.45 (s, 2H), 9.35 (d, J = 2.Hz, 1H), 8.78-8.77 (m, 2H), 8.75 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 7.(s, 1H), 4.85 (d, J = 5.6 Hz, 2H), 3.46 (brd, J = 7.2 Hz, 4H), 2.36-2.31 (m, 1H), 1.(brs, 2H), 1.86-1.81 (m, 2H), 1.26 (brs, 2H), 1.16 (s,2H), 1.14 (d, J = 2.8 Hz, 2H) ppm 451 587.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.75-9.72 (m, 1H), 9.40 (s, 1H), 9.35 (d, J = 2.Hz, 1H), 8.78 (d, J = 2.0 Hz, 1H), 8.68 - 8.61 (m, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.(s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.04(d, J = 8.4 Hz, 1H), 4.84 (d, J = 5.6 Hz, 2H), 4.32 (br d, J = 12.0 Hz, 2H), 3.69-3.65 (m, 2H), 3.47-3.44 (m, 4H), 2.52 (br d, J = 2.4 Hz, 2H), 1.94(br s, 2H), 1.85-1.81 (m, 2H), 1.25 (br s, 2H), 1.22 (d, J = 6.4 Hz, 6H) ppm 452 516.2 1H NMR (400 MHz, METHANOL-d4) 5 = 9.32 (s, 1H), 9.26 (d, J = 2.4 Hz, 1H), 8.(d, J = 2.0 Hz, 1H), 8.71 - 8.66 (m, 1H), 8.63 - 8.57 (m, 1H), 8.50 (s, 1H), 8.36 - 8.34 (m, 1H), 8.01 (s, 1H), 7.80 - 7.78 (m, 1H), 7.41 - 7.35 (m, 1H), 5.13 (d, J = 1.Hz, 2H), 4.95 (s, 2H), 4.46-4.42 (m, 1H), 4.18-4.14 (m, 1H), 3.63- 3.54 (m, 1H), 2.25-2.15 (m, 1H), 1.32 (d, J = 7.2 Hz, 3H), 1.18 -1.14 (m, 2H), 1.09- 1.03 (m, 2H) ppm 251 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 453 537.1 1H NMR (400 MHz, METHANOL-d4) 6 = 9.32 (s, 1H), 8.74 - 8.64 (m, 1H), 8.64 - 8.56 (m, 1H), 8.47 (s, 1H), 8.21 (d, J = 7.2 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.97 (s, 1H), 7.84 - 7.82 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.24 - 5.14 (m, 1H), 5.12 - 5.(m, 1H), 4.93 (s, 2H), 4.59 - 4.51 (m, 2H), 4.38 - 4.36(m, 1H), 4.12 - 4.07 (m, 1H), 3.57 - 3.46 (m, 1H), 1.46 - 145 (m, 3H), 1.29 (d, J = 7.2 Hz, 3H) ppm 454 614.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.40 (s, 1H), 8.72 - 8.60 (m, 2H), 8.57 (d, J = 2.0 Hz, 1H), 8.33 - 8.30 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.80 (s, 1H), 7.75 - 7.71 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.49 (d, J = 8.0 Hz, 1H), 4.39 - 4.26 (m, 3H), 4.21 - 4.14 (m, 1H), 3.74 - 3.58 (m, 4H), 2.54 - 2.52 (m, 2H), 1.59 - 1.45 (m, 1H), 1.21 (d, J = 6.4 Hz, 6H), 0.82 - 0.69 (m, 2H), 0.61 - 0.59 (m, 1H), 0.39 - 0.22 (m, 1H) ppm 455 516.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.32 (s, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.(d, J = 2.0 Hz, 1H), 8.72 - 8.65 (m, 1H), 8.63 - 8.56 (m, 1H), 8.50 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.00 (s, 1H), 7.84 - 7.76 (m, 1H), 7.38 (d, J = 7.2 Hz,1H), 5.13 (d, J 1.6 Hz, 2H), 4.95 (s, 2H), 4.46 - 4.42 (m, 1H), 4.18 - 4.14 (m, 1H), 3.64- 3.53 (m, 1H), 2.26 - 2.14 (m, 1H), 1.32 (d, J = 7.2 Hz, 3H), 1.20-1.12 (m, 2H), 1.12-1.01 (m, 2H) ppm 456 602.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.49 - 9.46 (m, 1H), 9.39 (s, 1H), 8.70 - 8.58 (m, 2H), 8.47 - 8.41 (m, 1H), 8.30 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.80 - 7.69 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 4.79 (brd, J = 6.0 Hz, 2H), 4.46 - 4.37 (m, 1H), 4.31 (br d, J = 11.4 Hz, 2H), 4.16 - 4.05 (m, 1H), 3.71 - 3.64 (m, 2H), 3.62 - 3.56 (m, 1H), 2.65 - 2.56 (m, 2H), 2.33 (s, 4H), 2.24 - 2.13 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.2 Hz, 6H) ppm 457 602.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.55 (m, 1H), 9.40 (s, 1H), 8.69 - 8.60 (m, 2H), 8.39 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 1.4 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.(s, 1H), 7.78 - 7.69 (m, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.10 - 4.95 (m, 2H), 4.81 (brd, J = 5.0 Hz, 2H), 4.35 - 4.24 (m, 3H), 3.99 - 3.97 (m, 1H), 3.71 - 3.59 (m, 3H), 2.53 - 2.52 (m, 2H), 2.48 - 2.46 (m, 3H), 1.21 (d, J = 6.2 Hz, 6H), 1.16 (d, J = 7.2 Hz, 3H) ppm 458 533.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.71 - 9.69 (m, 1H), 9.40 (s, 1H), 8.72 - 8.65 (m, 1H), 8.65 - 8.57 (m, 1H), 8.39 (d, J = 1.2 Hz, 1H), 8.37 - 8.30 (m, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.90 - 7.80 (m, 2H), 7.46 (d, J = 7.6 Hz, 1H), 5.13 - 5.02 (m, 1H), 5.00 - 4.91 (m, 1H), 4.82 (d, J = 5.2 Hz, 2H), 4.30 - 4.27 (m, 1H), 4.04 - 4.01 (m, 1H), 3.- 3.67 (m, 1H), 2.28-2.18 (m, 1H), 1.17 (d, J-7.2 Hz, 3H), 1.13-1.07 (m, 2H), 1.07 - 1.00 (m, 2H) ppm 252 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 459 614.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.70 - 9.58 (m, 1H), 9.4Q (s, 1H), 8.72 - 8.60 (m, 2H), 8.56 (d, J = 2.0 Hz, 1H), 8.41 (s, 1H), 8.34 - 8.27 (m, 1H), 8.07 (d, J = 8.0 Hz,1H), 7.91 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.69 (m, 1H), 7.03 (d, J = 8.4 Hz,1H), 4.82 (d, J = 5.6 Hz, 2H), 4.49 (d, J = 8.0 Hz, 1H), 4.37 - 4.27 (m, 3H), 4.23 -4.11 (m, 1H), 3.72 - 3.60 (m, 4H), 2.52 (br d, J = 2.0 Hz, 2H), 1.58 - 1.42 (m, 1H),1.21 (d, J = 6.4 Hz, 6H), 0.74 (brd, J = 8.0 Hz, 2H), 0.66 - 0.56 (m, 1H), 0.38 - 0.(m, 1H) ppm 460 568.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.71 - 9.60 (m, 1H), 9.39 (s, 1H), 8.74 - 8.60 (m, 2H), 8.54 (s, 1H), 8.41 (brs, 1H), 8.32- 8.23 (m, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.(s, 1H), 7.75 - 7.68 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.40 - 6.02 (m, 1H), 4.98 (s, 2H), 4.82 (brd, J = 5.6 Hz, 2H), 4.25 - 4.21 (m, 2H), 3.92 - 3.80 (m, 2H), 3.73 - 3.(m, 2H), 3.11 (s, 3H), 2.29 -2.12 (m, 2H) ppm 461 602.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.49 - 9.47 (m, 1H), 9.39 (s, 1H), 8.76 - 8.59 (m, 2H), 8.30 (d, J = 2.2 Hz, 1H), 8.21 (d, J = 1.8 Hz, 1H), 8.16 (s, 1H), 7.90 (d, J = 7.Hz, 1H), 7.81 - 7.69 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.79 (br d, J = 5.6 Hz, 2H), 4.48 - 4.37 (m, 1H), 4.31 (br d, J = 11.2 Hz, 2H), 4.18- 4.03 (m, 1H), 3.73 - 3.(m, 2H), 3.63 - 3.55 (m, 1H), 2.54 (br s, 2H), 2.33 (s, 3H), 2.29 - 2.13 (m, 2H), 1.(d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.2 Hz, 6H) ppm 462 602.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.57 - 9.55 (m, 1H), 9.40 (s, 1H), 8.76 - 8.56 (m, 2H), 8.39 (d, J = 1.5 Hz, 1H), 8.33 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 7.Hz, 1H), 7.82 (s, 1H), 7.74 - 7.72 (m, 1H), 7.03 (d, J = 8.6 Hz, 1H), 5.04 - 5.02 (m, 2H), 4.81 (br d, J = 5.6 Hz, 2H), 4.44 - 4.21 (m, 3H), 3.99 - 3.97 (m, 1H), 3.72 - 3.(m, 3H), 2.54 (br s, 2H), 2.47 (br s, 3H), 1.21 (d, J = 6.2 Hz, 6H), 1.16 (d, J = 7.Hz, 3H) ppm 463 544.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.63 - 9.50 (m, 1H), 9.05 - 8.97 (m, 1H), 8.56 - 8.49 (m, 1H), 8.36 - 8.30 (m, 1H), 8.26 - 8.24 (m, 1H), 8.14 (d, J = 9.4 Hz, 1H), 8.(d, J = 9.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 4.98 (s, 2H), 4.73 (brd, J = 5.6 Hz, 2H), 4.26 - 4.21 (m, 2H), 4.14-4.10 (m, 2H), 3.71 - 3.68 (m, 2H), 2.74 (s, 2H), 2.32 (s, 3H), 2.21 (s, 3H), 1.98 - 1.88 (m, 2H) ppm 464 552.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.04 (s, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.77 - 8.72 (m, 2H), 8.62 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.(s, 1H), 7.65 (d, J =7.6 Hz, 1H), 5.07 - 5.02 (m, 2H), 4.95 (s, 2H), 4.39 (d, J = 13.Hz, 1H), 4.12 - 4.07 (m, 1H), 3.48 - 3.46 (m, 1H), 3.27 - 3.26 (m, 1H), 2.59 -2.54 (m, H), 2.07 - 2.03 (m, 1H), 1.28 (d, J = 7.2 Hz, 1H) ppm 465 552.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.04 (s, 1H), 8.93 (d, J = 5.2 Hz, 1H), 8.77 - 8.72 (m, 2H), 8.62 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.(s, 1H), 7.65 (d, J =7.6 Hz, 1H), 5.07 - 5.01 (m, 2H), 4.95 (s, 2H), 4.38 (d, J = 13.Hz, 1H), 4.12 - 4.07 (m, 1H), 3.48 - 3.47 (m, 1H), 3.27 - 3.25 (m, 1H), 2.59 -2.54 (m, H), 2.07 - 2.03 (m, 1H), 1.27 (d, J = 7.2 Hz, 1H) ppm 253 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 466 558.25 1H NMR (400 MHz, DMSO-d6) 6 9.63 (t, J = 5.9 Hz, 1H), 9.36 (s, 1H), 8.62 (d, J = 1.4 Hz, 2H), 8.54 (d, J = 1.8 Hz, 1H), 8.27 (dd, J = 7.7, 1.8 Hz, 1H), 7.87 - 7.64 (m, 3H), 7.47 (d, J = 7.4 Hz, 1H),4.98(s, 1H), 4.81 (d,J=5.8 Hz, 1H), 4.28 - 4.19 (m, 2H), 4.19 4.08״ (m, 1H), 3.92 (td, J = 9.6, 9.1,4.8 Hz, 1H), 3.82 (dd, J = 11.0, 3.Hz, 2H), 3.69 (t, J = 4.8 Hz, 2H), 3.30 (s, 1H), 3.24 (d, J = 16.8 Hz, 2H), 3.09 (dd, J = 17.3, 8.8 Hz, 1H), 2.62-2.55 (m, 1H). 467 544.2 1H NMR (400 MHz, EW9897-1831-P1A,DMSO-d6) 6 = 9.63 (t, J = 5.8 Hz, 1H), 9.36 (s, 1H), 8.62 (s, 2H), 8.54 (d, J = 1.8 Hz, 1H), 8.45 - 8.42 (m, 1H), 8.27 (dd, J = 1.8, 7.8 Hz, 1H), 7.77 (s, 1H), 7.74 (dd, J = 2.0, 7.7 Hz, 2H), 7.36 (d, J = 7.3 Hz, 1H), 4.98 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.26 - 4.21 (m, 2H), 3.71 - 3.64 (m, 3H), 3.20 (s, 3H), 2.90 - 2.70 (m, 2H), 1.93 - 1.74 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H) ppm 468 544.2 1H NMR (400 MHz, EW9897-1831-P2A,DMSO-d6) 6 = 9.62 (bri, J = 5.8 Hz, 1H), 9.36 (s, 1H), 8.63 (s, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.43 (brs, 1H), 8.27 (dd, J = 1.6, 7.8 Hz, 1H), 7.77 (s, 1H), 7.74 (dd, J = 2.0, 7.7 Hz, 2H), 7.36 (d, J = 7.4 Hz, 1H), 4.98 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.26 - 4.21 (m, 2H), 3.71 - 3.64 (m, 3H), 3.20 (s, 3H), 2.87 - 2.70 (m, 2H), 1.93 - 1.75 (m, 2H), 1.19 (d, J = 6.5 Hz, 3H) 469 530.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.57 - 9.54 (m, 1H), 8.98 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.38 - 8.37 (m, 1H), 8.26 - 8.24 (m, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.89 - 7.87 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.37 - 7.34 (m, 1H), 6.65 (d, J = 9.2 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 4.18 - 3.(m, 2H), 3.73 - 3.63 (m, 2H), 2.75 - 2.68 (m, 2H), 1.89 - 1.77 (m, 2H), 1.69 (d, J = 4.0 Hz, 2H) ppm 470 574.4 1H NMR (400 MHz, METHANOL־d4) 5 = 9.33 (s, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.- 8.60 (m, 2H), 8.24 - 8.22 (m, 1H), 7.99 (s, 1H), 7.88 (d, J = 7.4 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.64 - 5.50 (m, 1H), 5.07 (s, 2H), 4.95 (s, 2H), 4.93 - 4.91 (m, 1H), 4.73 - 4.71 (m, 1H), 4.61 - 4.59 (m, 1H), 4.47 - 4.45 (m, 1H), 4.40 - 4.31 (m, 2H), 3.57 - 3.53 (m, 2H), 3.44 - 3.37 (m, 1H), 2.92 - 2.87 (m, 3H), 1.19 (d, J = 6.8 Hz, 3H) ppm 471 574.4 1H NMR (400 MHz, METHANOL-d4) 5 = 9.34 (s, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.- 8.59 (m, 2H), 8.24 - 8.22 (m, 1H), 7.99 (s, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.64 - 5.50 (m, 1H), 5.07 (s, 2H), 4.95 (s, 2H), 4.94 (brs, 1H), 4.73 - 4.71 (m, 1H), 4.61 - 4.59 (m, 1H), 4.47 - 4.45 (m, 1H), 4.39 - 4.34 (m, 2H), 3.58 - 3.53 (m, 2H), 3.43 - 3.37 (m, 1H), 2.89 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H) ppm 254 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 472 543.2 1H NMR (40Q MHz, DMSO-d6) 6 = 9.64 (s, 1H), 9.42 (s, 1H), 8.74 - 8.69 (m, 1H), 8.68 - 8.64 (m, 1H), 8.54 (d5 J = 1.6 Hz, 1H), 8.41 (d, J = 7.2 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.29 - 4.15 (m, 4H), 3.88 - 3.78 (m, 2H), 3.72 - 3.66 (m, 2H), 2.31 - 2.28 (m, 1H), 1.48 - 1.45 (m, 1H), 1.08 - 1.06 (m, 1H) ppm 473 566.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.59 (s, 1H), 9.13 (s, 1H), 8.53 (d, J = 1.6 Hz,1H), 8.39 (s, 1H), 8.29 - 8.25 (m, 2H), 8.25 - 8.23 (m, 1H), 7.95 (d, J = 9.2 Hz, 1H),7.79 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.32 - 6.84 (m, 1H), 4.98 (s, 2H),4.75 (d, J = 5.6 Hz, 2H), 4.24 - 4.22 (m, 2H), 4.19 - 4.13 (m, 2H), 3.72 - 3.65 (m, 2H), 2.91 - 2.88 (m, 2H), 2.03 - 1.95 (m, 2H) ppm 474 610.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.31 (s, 1H), 8.70 - 8.63 (m, 2H), 8.62 - 8.55 (m, 1H), 8.46 (br d,J=1.2 Hz, 1H), 8.23 - 8.21 (m, 1H), 7.97 (s, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.79 - 7.70 (m, 2H), 6.96 (d, J = 8.6 Hz, 1H), 4.93 (s, 2H), 4.32 - 4.31 (m, 2H), 3.93 - 3.91 (m, 2H), 3.77 - 3.75 (m, 2H), 3.21 (s, 3H), 2.56 - 2.54 (m, 2H), 1.68 - 1.65 (m, 3H), 1.29 (d, J = 6.2 Hz, 6H) ppm 475 590.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.33 (s, 1H), 8.72 - 8.56 (m, 3H), 8.24 - 8.22 (m, 1H), 8.09 - 7.86 (m, 3H), 7.75 - 7.73 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.- 6.48 (m, 1H), 4.95 (s, 2H), 4.28 - 4.26 (m, 2H), 3.86 - 3.71 (m, 2H), 3.21 - 3.16 (m, 3H), 2.58 -2.56 (m, 2H), 2.29 - 2.11 (m, 3H), 1.31 (d, J = 6.2 Hz, 6H) ppm 476 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.60 (m, 1H), 9.36 (s, 1H), 8.67 - 8.58 (m, 2H), 8.54 (d, J 1.8 Hz, 1H), 8.42 - 8.31 (m, 1H), 8.27 - 8.25 (m, 1H), 7.87 - 7.(m, 3H), 7.36 (d, J = 7.4 Hz, 1H), 4.98 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.33 - 4.15 (m, 2H), 3.81 - 3.60 (m, 3H), 3.54 - 3.48 (m, 1H), 3.43 - 3.41 (m, 1H), 3.31 - 3.29 (m, 3H), 3.26 (s, 3H), 2.85 - 2.69 (m, 2H), 2.08 - 1.98 (m, 1H), 1.81 - 1.71 (m, 1H) ppm 477 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.60 (m, 1H), 9.36 (s, 1H), 8.72 - 8.58 (m, 2H), 8.54 (d, J = 1.8 Hz, 1H), 8.38 (s, 1H), 8.27- 8.25 (m, 1H), 7.93-7.61 (m, 3H), 7.37 (d, J = 7.4 Hz, 1H), 4.98 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.29-4.16 (m, 2H), 3.74 - 3.63 (m, 3H), 3.55 - 3.49 (m, 1H), 3.46 - 3.42 (m, 1H), 3.30 (s, 3H), 3.(s, 3H), 2.84 - 2.69 (m, 2H), 2.06 - 1.99 (m, 1H), 1.81 - 1.72 (m, 1H) ppm 478 550.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57- 9.55 (m, 1H), 9.10 (s, 1H), 8.53 (d, J =1.8 Hz, 1H), 8.34 (s, 1H), 8.28 - 8.19 (m, 2H), 8.07 (d, J = 5.4 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.20 (d, J = 5.4 Hz, 1H), 4.98 (s, 2H), 4.74 (d, J = 6.0 Hz, 2H), 4.26 - 4.19 (m, 2H), 4.18 - 4.12 (m, 2H), 3.72 - 3.(m, 2H), 2.87 - 2.85 (m, 2H), 2.04 - 1.96 (m, 2H) ppm 255 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 479 595.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.31 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.(d, J = 8.0 Hz, 1H), 8.22 - 8.19 (m, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.(d, J = 7.6 Hz, 1H), 7.03 - 6.91 (m, 3H), 5.04 (s, 2H), 4.92 (s, 2H), 4.39 - 4.29 (m, 2H), 4.25 - 4.20 (m, 2H), 3.76 - 3.69 (m, 2H), 3.58 - 3.50 (m, 4H), 1.73 -1.64 (m, 3H) ppm 480 560.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.65-9.64 (m, 1H), 9.40 (s, 1H), 8.66 (s, 2H), 8.55 (d, J = 1.6 Hz, 1H), 8.40 (brs, 1H), 8.28-8.26 (m, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.82 (s, 1H), 7.79 - 7.74 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H), 4.83 (br d, J = 5.6 Hz, 2H), 4.26 - 4.21 (m, 2H), 3.73 - 3.67 (m, 2H), 3.43-3.42 (m 1H), 3.38 (s, 3H), 3.20 (s, 3H), 2.73-2.72 (m, 1H), 1.23-1.22 (m, 1H), 0.95 - 0.88 (m, 1H) ppm 481 557.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.70- 9.55 (m, 1H), 9.19 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.36-8.26 (m, 1H), 8.25 - 8.17 (m, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.65- 7.54 (m, 2H), 7.37 (d, J = 8.2 Hz, 1H), 6.71 - 6.64 (m, 2H), 4.97 (s , 2H), 4.76 (br d, J = 5.4 Hz, 2H), 4.28 (br d, J = 4.2 Hz, 4H), 4.24 - 4.20 (m, 2H), 3.69 - 3.66 (m, 2H), 1.94 - 1.83 (m, 1H), 0.97 - 0.89 (m, 2H), 0.69 - 0.62 (m, 2H) ppm 482 616.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.58 - 9.55 (m, 1H), 9.40 (s, 1H), 8.73 - 8.57 (m, 2H), 8.47 (d, J = 1.6 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.(s, 1H), 7.77 - 7.71 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.(d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.2 Hz, 2H), 3.78 - 3.61 (m, 3H), 3.58 - 3.50 (m, 1H), 3.50 - 3.37 (m, 5H), 2.52 (s, 2H), 2.30 - 2.19 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H), 1.03 - 1.00 (m, 3H) ppm 483 572.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.60 - 9.57 (m, 1H), 9.40 (s, 1H), 8.70 - 8.58 (m, 2H), 8.45 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.Hz, 1H), 7.79 (s, 1H), 7.74 - 7.68(m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.Hz, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.2 Hz, 2H), 3.73 - 3.59 (m, 3H), 3.59-3.51 (m, 1H), 3.26 (s, 2H), 2.52 (s, 2H), 2.23 - 2.10 (m, 1H), 1.38 (d, J = 7.Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 484 622.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.63 (m, 1H), 9.40 (s, 1H), 8.73 - 8.59 (m, 2H), 8.53 - 8.36 (m, 2H), 7.91 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.75 - 7.73 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 5.2 Hz, 2H), 4.56 - 4.47 (m, 1H), 4.31 (d, J = 11.6 Hz, 2H), 4.26 -4.17 (m, 1H), 3.76 - 3.62 (m, 3H), 2.54 - 2.52 (m, 2H), 2.41 - 2.34 (m, 1H), 2.30 - 2.18 (m, 1H), 1.35 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.0 Hz, 6H) ppm 485 616.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.55 (m, 1H), 9.40 (s, 1H), 8.71 - 8.58 (m, 2H), 8.50 - 8.45 (m, 1H), 8.20 - 8.18 (m, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.84 - 7.(m, 3H), 7.03 (d, J = 8.2 Hz, 1H), 4.81 (br d, J = 5.6 Hz, 2H), 4.32 (br d, J 11.Hz, 2H), 3.77 - 3.63 (m, 3H), 3.57 - 3.52 (m, 1H), 3.49 - 3.39 (m, 5H), 2.54 - 2.(m, 2H), 2.31 - 2.21 (m, 2H), 1.22 (d, J = 6.2 Hz, 6H), 1.02 - 1.00 (m, 3H) ppm 256 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 486 622.2 1H NMR (40Q MHz, DMSO-d6) 6 = 9.64 - 9.63 (m, 1H), 9.4Q (s, 1H), 8.73 - 8.59 (m, 2H), 8.53 - 8.36 (m, 2H), 7.92 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.75 - 7.73 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.81 (d, J = 5.2 Hz, 2H), 4.56-4.47 (m, 1H), 4.31 (d, J = 11.6 Hz, 2H), 4.26 -4.17 (m, 1H), 3.76 - 3.62 (m, 3H), 2.54 - 2.52 (m, 2H), 2.41 - 2.34 (m, 1H), 2.30 - 2.17 (m, 1H), 1.34 (d, J = 7.0 Hz, 3H), 1.20 (d, J = 6.0 Hz, 6H) ppm 487 491.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.65 (m, 1H), 9.42 (s, 1H), 8.74 - 8.62 (m, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.27 - 8.25 (m, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.92 - 7.90 (m, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.(s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.26 -4.19 (m, 2H), 4.04 (s, 3H), 3.72 - 3.64 (m, 2H) ppm 488 530.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.35 (s, 1H), 8.62 (s, 2H), 8.53 (d. J = 1.6 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.84 - 7.65 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.80 (d, J = 5.6 Hz, 2H), 4.28 - 4.19 (m, 2H), 3.73 - 3.(m, 2H), 3.44 - 3.38 (m, 2H), 3.19 (s, 3H), 2.79 - 2.76 (m, 2H), 1.97 - 1.84 (m, 2H) ppm 489 555.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.45 (s, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.64 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.48 (s, 1H), 8.36 - 8.22 (m, 2H), 8.13 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.36- 6.86 (m, 1H), 4.99 (s, 2H), 4.83 (brd, J = 5.6 Hz, 2H), 4.63 - 4.60 (m, 2H), 4.27 - 4.19 (m, 2H), 3.74 - 3.64 (m, 2H), 1.47 - 1.40 (m, 3H) ppm 49Q 572.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.59 - 9.57 (m, 1H), 9.40 (s, 1H), 8.72 - 8.58 (m, 2H), 8.49-8.46 (m, 1H), 8.43 (d, J = 1.8 Hz, 1H), 8.18-8.16 (m, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.82 - 7.64 (m, 3H), 7.03 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 5.8 Hz, 2H), 4.31 (br d, J = 11.2 Hz, 2H), 3.79 - 3.48 (m, 4H), 3.29 (br s, 2H), 2.53 (br d, J = 2.Hz, 2H), 2.23 - 2.04 (m, 1H), 1.38 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 6.2 Hz, 6H) ppm 491 532.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.50 (m, 1H), 9.08 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.44 - 8.39 (m, 1H), 8.32 - 8.22 (m, 3H), 7.81 - 7.69 (m, 2H), 7.48 (s, 1H), 7.20 (s, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.32 (s, 4H), 4.27 - 4.19 (m, 2H), 3.73 - 3.65 (m, 2H), 2.25 (s, 3H) ppm 492 545.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.49 (m, 1H), 8.97 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.36 (s, 1H), 8.29 - 8.21 (m, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.21 - 7.10 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.(d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.70 (d, J = 5.8 Hz, 2H), 4.28 - 4.16 (m, 2H), 4.09 - 3.99 (m, 2H), 3.82 (s, 3H), 3.74 - 3.64 (m, 2H), 2.69 - 2.63 (m, 2H), 1.93 - 1.81 (m, 2H) ppm 257 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 493 539.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.61 (m, 1H), 9.47 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.24 - 8.21 (m, 1H), 8.00 - 7.98 (m, 2H), 7.(s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 4.97 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.34 - 4.31 (m, 2H), 4.24 - 4.19 (m, 2H), 3.67 (br s, 2H), 1.33 - 1.30 (m, 3H) ppm 494 606.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.62-9.60 (m, 1H), 9.39 (s, 1H), 8.67-8.61 (m, 2H), 8.28 - 8.27 (m, 1H), 8.23-8.20 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.80 (s, 1H), 7.76-7.74 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.80 (brd, J = 5.6 Hz, 2H), 4.32-4.(m, 3H), 3.69-3.65 (m, 4H), 2.53 (br d, J = 2.4Hz, 2H), 2.30 -2.18 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.4 Hz, 6H) ppm 495 606.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.62-9.60 (m, 1H), 9.39 (s, 1H), 8.67-8.61 (m, 2H), 8.28 - 8.27 (m, 1H), 8.23-8.20 (m, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.80 (s, 1H), 7.76-7.74 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.81 (brd, J = 5.6 Hz, 2H), 4.32-4.(m, 3H), 3.69-3.65 (m, 4H), 2.53 (brd, J = 2.4Hz, 2H), 2.30 - 2.18 (m, 2H), 1.45 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 496 546.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.59-9.56 (m, 1H), 9.09 (s, 1H), 8.53 (s, 1H), 8.24-8.21 (m, 3H), 8.02 (d, J = 9.2 Hz, 1H), 7.76-7.72 (m, 2H), 7.51 (s, 1H), 7.10- 7.08 (m, 1 H), 4.97 (s, 2H),4.74 (d, J = 6.0 Hz, 2H), 4.43 - 4.35 (m, 2H), 4.23 - 4.(m, 2H), 3.90 - 3.82 (m, 1H), 3.69 - 3.66 (m, 2H), 3.36 (s, 3H), 2.14 - 2.06 (m, 2H) ppm 497 537.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.42 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.47 - 8.41 (m, 1H), 8.29 - 8.27 (m, 1H), 8.24 - 8.21 (m, 1H), 7.89 - 7.80 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.82 (d, J = 5.2 Hz, 2H), 4.62 - 4.59 (m, 2H), 4.30 - 4.27 (m, 1H), 4.04-4.02 (m, 1H), 3.70 - 3.60 (m, 1H), 1.46-1.43 (m, 3H), 1.16 (d, J = 7.2 Hz, 3H) ppm 498 587.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.39 (s, 1H), 9.28 - 9.26 (m, 1H), 8.69 - 8.60 (m, 2H), 8.42 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.07 - 8.06 (m, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.78 - 7.70 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.32 (brd, J-11 .2 Hz, 2H), 3.96 - 3.95 (m, 1H), 3.76 - 3.61 (m, 4H), 3.11 (s, 3H), 2.53 (br s, 2H), 1.27 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.2 Hz, 6H) ppm 499 517.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64-9.63 (m, 1H), 9.39 (s, 1H), 8.67 (d, J = 8.Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.27-8.25 (m, 1H), 8.(d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.75-7.70 (m, 2H), 4.98 (s, 2H), 4.82 (d, J = 6.Hz, 2H), 4.36-4.34 (m, 2H), 4.24 - 4.21 (m, 2H), 3.69-3.67 (m, 2H), 2.88-2.85 (m, 2H), 1.98-1.95 (m, 2H) ppm 258 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 500 558.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.54 - 9.51 (m, 1H), 9.4Q (s, 1H), 8.65 - 8.61 (m, 2H), 8.42 (s, 1H), 8.39 (d, J=1.2 Hz, 1H), 8.24 - 8.21 (m, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.82 (s, 1H), 7.74 - 7.72 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H),7.03 (d, J = 8.4 Hz, 1H), 4.81 (d, J = 5.6 Hz, 2H), 4.31 (brd, J = 11.0 Hz, 2H), 3.- 3.75 (m, 1H), 3.68 - 3.65 (m, 2H), 3.62 - 3.54 (m, 1H), 3.05 - 2.95 (m, 1H), 2.54 - 2.52 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 501 519.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.61 (m, 1H), 9.39 (s, 1H), 8.70 - 8.65 (m, 1H), 8.64 - 8.56 (m, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.48 - 8.36 (m, 1H), 8.27- 8.(m, 1H), 8.12 (d, J = 7.4 Hz, 1H), 7.80 (s, 1H), 7.77 - 7.69 (m, 2H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.54 (q, J = 7.2 Hz, 2H), 4.28 - 4.20 (m, 2H), 3.73 - 3.(m, 2H), 2.23 (s, 3H), 1.43 - 1.41 (m, 3H) ppm 502 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.54 - 9.52 (m, 1H), 9.40 (s, 1H), 8.64 - 8.61 (m, 2H), 8.39 (s, 1H), 8.24 - 8.21 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.74 - 7.72 (m, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.81 (brd, J = 5.Hz, 2H), 4.31 (br d, J = 11.6 Hz, 2H), 3.82 - 3.53 (m, 4H), 3.00 - 2.98 (m, 1H), 2.- 2.54 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.2 Hz, 6H) ppm 503 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.56 (m, 1H), 9.08 (s, 1H), 8.52 (d, J =1.6 Hz, 1H), 8.29 - 8.23 (m, 3H), 7.79 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H),7.47 (s, 1H), 6.99 (d, J = 2.0 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.31 (s, 4H), 4.26-4.19 (m, 2H), 3.73-3.64 (m, 2H), 1.98- 1.85 (m, 1H), 1.00- 0.90 (m, 2H), 0.75 - 0.65 (m, 2H) ppm 504 530.1 1H NMR (400 MHz, METHANOL-d4) 5 = 9.58 - 9.55 (m, 1H), 9.06 (s, 1H), 8.53 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.90 (d, J = 9.Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.49 (s, 1H), 7.08 - 7.07 (m, 1H), 4.97 (s, 2H), 4.73 (d, J = 6.4 Hz, 1H), 4.24 - 4.08 (m, 4H), 3.69 - 3.66 (m, 2H), 2.-2.96 (m, 1H), 2.12-2.07 (m, 1H), 1.67- 1.62 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H) ppm 505 622.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.63 (m, 1H), 9.40 (s, 1H), 8.72 - 8.59 (m, 2H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.(s, 1H), 7.77 - 7.75 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.(d, J = 11.6 Hz, 2H), 4.28 - 4.20 (m, 1H), 3.74 - 3.62 (m, 4H), 2.54 (s, 2H), 2.39 - 2.33 (m, 1H), 2.23 - 2.14 (m, 1H), 1.51 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 506 622.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.62 (m, 1H), 9.39 (s, 1H), 8.71 - 8.59 (m, 2H), 8.47 - 8.36 (m, 2H), 7.90 (d, J = 7.4 Hz, 1H), 7.83 - 7.70 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.38 - 4.18 (m, 3H), 3.73 - 3.59 (m, 4H), 2.(brd, J = 2.6 Hz, 2H), 2.40 - 2.33 (m, 1H), 2.23 - 2.15 (m, 1H), 1.51 (d, J = 6.2 Hz, 3H), 1.21 (d, J = 6.2 Hz, 6H) ppm 259 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 507 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.53 - 9.39 (m, 2H), 8.76 - 8.58 (m, 2H), 8.(d, J = 1.8 Hz, 1H), 8.46 (brs, 1H), 8.36 -8.34 (m, 1H), 8.26 - 8.24 (m, 1H), 7.99 (s, 1H), 7.87 - 7.85 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.47 - 7.45 (m, 1H), 5.67 - 5.(m, 1H), 4.98 (s, 2H), 4.35 - 4.13 (m, 2H), 3.92 (d, J = 6.6 Hz, 2H), 3.73 - 3.60 (m, 2H), 3.34 (s, 3H), 2.28-2.19 (m, 1H), 1.13-1.01 (m, 4H) ppm 508 568.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.60 - 9.59 (m, 1H), 9.16 (s, 1H), 8.53 (d, J =1.6 Hz, 1H), 8.43 (s, 1H), 8.39 - 8.33 (m, 1H), 8.32 - 8.28 (m, 1H), 8.25 (d, J = 7.Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 - 7.47 (m, 2H), 7.- 6.85 (m, 1H), 4.98 (s, 2H), 4.75 (d, J = 5.6 Hz, 2H), 4.43 - 4.38 (m, 2H), 4.38 - 4.32 (m, 2H), 4.26 - 4.19 (m, 2H), 3.74 - 3.62 (m, 2H) ppm 509 587.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.74- 9.72 (m, 1H), 9.39 (s, 1H), 9.25 (d, J = 2.4 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.68 - 8.59 (m, 2H), 8.42 (s, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.85 (s, 1H), 7.80 - 7.68 (m, 1H), 7.09 - 6.96 (m, 1H), 4.82 (br d,J= 5.4 Hz, 2H), 4.31 (br d, J = 11.2 Hz, 2H), 3.67 - 3.64 (m, 2H), 3.54 (br s, 1H), 3.28 - 3.22 (m, 2H), 2.51 (br s, 2H), 2.30 -2.17 (m, 1H), 2.07 - 1.85 (m, 2H), 1.79 -1.(m, 1H), 1.27 - 1.17 (m, 9H) ppm 510 574.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.56 (m, 1H), 9.04 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.37 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54 - 7.41 (m, 2H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.26 - 4.20 (m, 2H), 4.17 - 4.09 (m, 2H), 3.73 - 3.64 (m, 2H), 3.54 - 3.52 (m, 2H), 3.25 (s, 3H), 2.80 - 2.78 (m, 4H), 1.99 - 1.90 (m, 2H) ppm 511 544.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 - 9.55 (m, 1H), 9.06 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.41 (s, 1H), 8.30 - 8.22 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 - 7.(m, 1H), 7.48 (s, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.21 - 7.13 (m, 1H), 4.98 (s, 2H), 4.80 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.27 - 4.18 (m, 2H), 3.72 - 3.64 (m, 2H), 3.34 - 3.33 (m, 3H) ppm 512 530.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.56 (m, 1H), 8.96 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.32 (s, 1H), 8.26 - 8.25 (m, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.38 - 7.35 (m, 2H), 7.22 (m, 1H), 7.09 - 7.02 (m, 1H), 6.81 - 6.80 (m, 1H), 6.67 - 6.61 (m, 1H), 4.98 (s, 2H), 4.70 (d, J = 5.8 Hz, 2H), 4.23 - 4.21 (m, 4H), 3.72 - 3.66 (m, 2H), 3.36 - 3.35 (m, 2H), 2.91 (s, 3H) ppm 513 550.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.59- 9.57 (m, 1H), 9.12 (s, 1H), 8.53 (d, J =1.8 Hz, 1H), 8.48 - 8.39 (m, 1H), 8.33 - 8.21 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.(d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.08 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H), 4.75 (d, J = 5.8 Hz, 2H), 4.28 - 4.19 (m, 2H), 4.18 - 4.07 (m, 2H), 3.- 3.64 (m, 2H), 2.82 - 2.80 (m, 2H), 2.01 - 1.92 (m, 2H) ppm 260 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 514 530.2 1H NMR (40Q MHz, DMSO-d6) 6 = 9.49 - 9.48 (m, 1H), 9.Q3 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 4.71 (d, J = 5.6 Hz, 2H), 4.33 - 4.23 (m, 2H), 4.16 - 4.07 (m, 2H), 3.66 - 3.58 (m, 2H), 2.80 - 2.78 (m, 2H), 2.31 - 2.26 (m, 2H), 2.25 (s, 3H), 1.99 - 1.89 (m, 2H) ppm 515 587.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.75 - 9.73 (m, 1H), 9.40 (s, 1H), 9.26 (d, J = 2.2 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.69 - 8.56 (m, 2H), 7.91 (d, J = 7.4 Hz, 1H), 7.86 (s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.83 (br d,J= 5.8 Hz, 2H), 4.31 (br d, J = 11.4 Hz, 2H), 3.79 - 3.62 (m, 2H), 3.60 - 3.43 (m, 1H), 3.30 (br s, 2H), 2.54-2.52 (m, 2H), 2.30-2.18 (m, 1H), 2.12-1.90 (m, 2H), 1.82- 1.60 (m, 1H), 1.26 -1.10 (m, 9H) ppm 516 606.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.70 - 9.67 (m, 1H), 9.40 (s, 1H), 8.72 - 8.58 (m, 2H), 8.45 (d, J = 1.6 Hz, 1H), 8.18-8.15 (m, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.78 - 7.69 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.53 - 5.48 (m, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.2 Hz, 2H), 4.27 - 4.20 (m, 1H), 4.03 - 3.85 (m, 2H), 3.- 3.63 (m, 3H), 2.53 - 2.52 (m, 2H), 1.62 - 1.60 (m, 3H), 1.21 (d, J = 6.0 Hz, 6H) ppm 517 602.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.63 (m, 1H), 9.40 (s, 1H), 8.71 - 8.57 (m,3H), 8.32 - 8.29 (m, 1H), 7.96 - 7.87 (m, 1H), 7.83 - 7.71 (m, 3H), 7.03 (d, J = 8.4Hz, 1H), 5.32 - 5.27 (m, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.6 Hz, 2H), 4.21 -4.11 (m, 1H), 4.00 - 3.94 (m, 1H), 3.72 - 3.63 (m, 2H), 3.61 - 3.49 (m, 1H),2.53 - 2.52 (m, 2H), 1.62 (d, J = 6.4 Hz, 3H), 1.26 -1.19 (m, 9H) ppm 518 602.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.40 (s, 1H), 8.71 - 8.56 (m, 3H), 8.43 - 8.36 (m, 1H), 8.32 - 8.29 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.82 - 7.(m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 5.30 (d, J = 6.4 Hz, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 (brd, J = 11.6 Hz, 2H), 4.21 -4.12 (m, 1H), 4.00- 3.94 (m, 1H), 3.69-3.(m, 2H), 3.56- 3.53 (m, 1H), 2.53 (brs, 2H), 1.62 (d, J = 6.8 Hz, 3H), 1.25-1.(m, 9H) ppm 519 555.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.63 (m, 1H), 9.45 (s, 1H), 8.80 - 8.65 (m, 2H), 8.53 (d, J = 1.6 Hz, 1H), 8.46 (s, 1H), 8.33 (d, J = 7.6 Hz, 1H), 8.29 - 8.27 (m,1H), 8.14 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.30 - 7.02 (m,1H), 4.97 (s, 2H), 4.84 (d, J = 5.6 Hz, 2H), 4.30 - 4.27 (m, 1H), 4.14 (s, 3H), 4.04 -3.99 (m, 1H), 3.71 - 3.60 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H) ppm 520 567.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.52 (m, 1H), 9.08 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.40 (s, 2H), 8.32 (d, J = 9.0 Hz, 1H), 8.24 (dd, J = 1.9, 7.8 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.45 (s, 1H), 7.14 (s, 1H), 7.12 - 6.81 (m, 2H), 4.99 - 4.97 (m, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.36 - 4.30 (m, 2H), 4.24 - 4.20 (m, 4H), 3.69 - 3.66 (m, 2H) ppm 261 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 521 566.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.57- 9.55 (m, 1H), 9.10 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.28 - 8.19 (m, 3H), 7.84 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.40 - 7.12 (m, 2H), 4.98 (s, 2H), 4.74 (d, J = 5.8 Hz, 2H), 4.23 - 4.(m, 2H), 4.18 - 4.12 (m, 2H), 3.72 - 3.61 (m, 2H), 2.92 - 2.90 (m, 2H), 1.99 - 1.(m, 2H) ppm 522 606.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.69 - 9.68 (m, 1H), 9.40 (s, 1H), 8.69 - 8.60 (m, 2H), 8.45 (d, J = 1.2 Hz, 1H), 8.17-8.15 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.82 (s, 1H), 7.78 - 7.72 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.53 - 5.48 (m, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.2 Hz, 2H), 4.27 - 4.20 (m, 1H), 4.02 - 3.86 (m, 2H), 3.- 3.61 (m, 3H), 2.53 - 2.52 (m, 2H), 1.62 - 1.60 (m, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 523 532.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.58- 9.56 (m, 1H), 9.11 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.34 - 8.24 (m, 3H), 8.24 - 8.23 (m, 1H), 7.92 - 7.90 (m, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.53 (s, 1H), 7.35 - 7.33 (m, 1H), 7.08 - 7.05 (m, 1H), 5.04 - 4.88 (m, 2H), 4.74 (br d, J = 5.8 Hz, 2H), 4.35 (s, 4H), 4.29 - 4.27 (m, 1H), 4.02 - 4.00 (m, 1H), 3.70 - 3.60 (m, 1H), 1.17 (d, J = 7.0 Hz, 3H) ppm 524 550.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.65- 9.63 (m, 1H), 9.10 (s, 1H), 8.38 (d, J = 1.4 Hz, 1H), 8.35- 8.26 (m, 2H), 8.17-8.15 (m, 1H), 7.91 -7.90 (m, 1H), 7.53 (s, 1H), 7.34 - 7.32 (m, 1H), 7.07 - 7.05 (m, 1H), 5.10 - 4.90 (m, 2H), 4.73 (br d, J = 5.Hz, 2H), 4.34 (s, 4H), 4.28 - 4.25 (m, 1H), 4.02 - 4.00 (m, 1H), 3.73-3.71 (m, 1H), 1.17 (d, J = 7.0 Hz, 3H) ppm 525 583.1 1H NMR (400 MHz, DMSO-d6) 0 = 9.57-9.54 (m, 1H), 9.03 (s, 1H), 8.50 (d, J = 1.Hz, 1H), 8.40 (brd, J = 2.4 Hz, 1H), 8.26-8.21 (m, 2H), 7.74 - 7.70 (m, 2H), 7.44 - 7.37(m, 4H), 4.96 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.23-4.20 (m, 2H), 4.00-3.97 (m, 2H), 3.67-3.65 (m, 2H), 2.82-2.79 (m, 2H), 1.98-1.92(m, 2H) ppm 526 534.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.70- 9.48 (m, 1H), 9.10 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.44 - 8.36 (m, 1H), 8.30 - 8.21 (m, 2H), 8.17 - 8.08 (m, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.03 - 6.92 (m, 1H), 4.98 (s, 2H), 4.74 (d, J = 6.0 Hz, 2H), 4.29 - 4.12 (m, 4H), 3.74 - 3.62 (m, 2H), 2.87 - 2.(m, 2H), 2.03 - 1.91 (m, 2H) ppm 527 540.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.02 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.- 8.43 (m, 1H), 8.26 - 8.18 (m, 2H), 7.67 - 7.63 (m, 2H), 7.60 (s, 1H), 7.54 - 7.47 (m, 3H), 5.06 (s, 2H), 4.85 (br s, 2H), 4.43 - 4.33 (m, 2H), 4.10 - 4.08 (m, 2H), 3.59 - 3.51 (m, 2H), 2.86 - 2.84 (m, 2H), 2.15 - 2.01 (m, 2H) ppm 262 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 528 585.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.71 - 9.66 (m, 1H), 9.4Q (s, 1H), 9.14 (d, J = 2.0 Hz, 1H), 8.70 - 8.60 (m, 3H), 7.91 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.77 - 7.(m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.83 (br d, J = 5.6 Hz, 2H), 4.32 (br d, J = 11.Hz, 2H), 3.81 - 3.75 (m, 2H), 3.69 - 3.67 (m, 2H), 2.58 - 2.53 (m, 4H), 1.99 -1.(m, 1H), 1.72- 1.67 (m, 1H), 1.54- 1.48 (m, 1H), 1.22 (d, J = 6.4 Hz, 6H), 0.74- 0.67 (m, 1H) ppm 529 531.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.64-9.63 (m, 1H), 9.39 (s, 1H), 8.66(d, J = 8.Hz, 1H), 8.54-8.50 (m, 2H), 8.27-8.25 (m, 1H), 8.14 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.75-7.70 (m, 2H), 4.98 (s, 2H), 4.82 (brd, J = 6.0 Hz, 2H), 4.41-4.39 (m, 1H), 4.24-4.21 (m, 2H), 3.69-3.67 (m, 2H), 2.92-2.84 (m, 2H), 2.08-2.03 (m, 1H), 1.71 - 1.66 (m, 1H), 1.42 (d, J = 6.4 Hz, 3H) ppm 530 573.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.75 - 9.73 (m, 1H), 9.45 (s, 1H), 8.78 - 8.73 (m, 1H), 8.71 - 8.66 (m, 1H), 8.47 - 8.43 (m, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.22 - 8.19 (m, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.31 - 7.(m, 1H), 5.11 - 5.03 (m, 1H), 5.00-4.93 (m, 1H), 4.84 (d, J = 5.2 Hz, 2H), 4.31 - 4.27 (m, 1H), 4.14 (s, 3H), 4.05 - 4.00 (m, 1H), 3.79 - 3.70 (m, 1H), 1.18 (d, J = 7.Hz, 3H) ppm 531 584.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.62 - 9.51 (m, 1H), 9.39 (s, 1H), 8.64 (q, J = 8.6 Hz, 2H), 8.42 (d, J = 1.8 Hz, 1H), 8.15 - 8.13 (m, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.79 (s, 1H), 7.75 - 7.73 (m, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.80 (d, J = 5.4 Hz, 2H), 4.31 (brd, J = 12.4 Hz, 2H), 3.68 - 3.66 (m, 2H), 3.16 - 3.14 (m, 2H), 2.52 (br s, 2H), 2.37 - 2.34 (m, 2H), 1.36- 1.29 (m, 2H), 1.21 (d, J = 6.2 Hz, 6H), 1.17 (brd, J = 2.0 Hz, 2H) ppm 532 565.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.56 - 9.54 (m, 1H), 9.02 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.38 (brs, 1H), 8.27 - 8.18 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.43-7.36 (m, 3H), 7.25 (d, J = 7.6 Hz, 1H), 7.12-6.79 (m, 1H), 4.97 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.28 - 4.17 (m, 2H), 4.00 (t, J = 6.4 Hz, 2H), 3.75 - 3.(m, 2H), 2.79 - 2.77 (m, 2H), 1.94 - 1.92 (m, 2H) ppm 533 549.1 1H NMR (400 MHz, METHANOL-d4) 5 = 8.94 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.- 8.18 (m, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.(d, J = 9.2 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.07 - 7.(m, 1H), 5.04 (s, 2H), 4.82 (s, 2H), 4.37 - 4.31 (m, 2H), 4.05 - 4.03 (m, 2H), 3.55 - 3.49 (m, 2H), 2.76 - 2.75 (m, 2H), 2.02 - 2.00 (m, 2H) ppm 534 560.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.60 (m, 1H), 9.38 (s, 1H), 8.65(s, 2H), 8.53(d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.27-8.25(m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.74-7.69(m, 2H), 7.09 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 4.82 (brd, J = 5.6 Hz, 2H), 4.23-4.21 (m, 2H), 3.69-3.66 (m, 2H), 3.53-3.50 (m, 2H), 3.25(s, 3H), 3.23 (s, 3H), 2.67-2.64 (m, 1H), 1.13-1.07 (m, 1H), 0.80-0.76 (m, 1H) ppm 263 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 535 602.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.4Q (s, 1H), 8.72 - 8.58 (m, 2H), 8.52 (s, 1H), 8.48 - 8.37 (m, 1H), 8.36 - 8.27 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.81 - 7.68 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 5.35 - 5.22 (m, 1H), 4.- 4.74 (m, 2H), 4.43 (d, J = 13.2 Hz, 1H), 4.31 (d, J = 12.4 Hz, 2H), 4.04 - 4.00 (m, 1H), 3.72 - 3.60 (m, 3H), 2.53 (d, J = 4.0 Hz, 2H), 1.63 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.0 Hz, 6H), 1.07 (d, J = 6.8 Hz, 3H) ppm 536 556.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.54 (m, 1H), 9.06 (s, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 7.Hz, 1H), 4.97 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.30 - 4.17 (m, 2H), 4.10 - 4.07 (m, 2H), 3.74 - 3.60 (m, 2H), 2.77 - 2.73 (m, 2H), 2.03 - 1.88 (m, 3H), 0.87 - 0.74 (m, 4H) ppm 537 588.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.60- 9.50 (m, 1H), 9.40 (s, 1H), 8.71 - 8.58 (m, 2H), 8.47 (d, J = 2.2 Hz, 1H), 8.44 (s, 1H), 8.34 - 8.32 (m, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.81 - 7.71 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.40 - 4.25 (m, 4H), 3.76 - 3.61 (m, 2H), 3.45 - 3.40 (m, 2H), 2.(br s, 2H), 2.13 - 1.96 (m, 2H), 1.67 - 1.56 (m, 2H), 1.21 (d, J = 6.2 Hz, 6H) ppm 538 530.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.50 - 9.48 (m, 1H), 9.03 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.47 - 7.44 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 4.27 - 4.25 (m, 2H), 4.11 - 4.09 (m, 2H), 3.63 - 3.61 (m, 2H), 2.77 - 2.74 (m, 2H), 2.34 (br s, 2H), 2.28 - 2.26 (m, 2H), 1.94 - 1.91 (m, 2H) ppm 539 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.53 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 8.25 - 8.23 (m, 1H), 8.15 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 9.6 Hz, 1H), 7.39 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.69 - 6.68 (m, 1H), 4.97 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 3.99 - 3.96 (m, 2H), 3.69 (s, 5H), 2.67 - 2.66 (m, 2H), 1.94 - 1.85 (m, 2H) ppm 540 602.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.65- 9.63 (m, 1H), 9.40 (s, 1H), 8.71 - 8.60 (m, 2H), 8.52 (d, J = 1.6 Hz, 1H), 8.38 - 8.34 (m, 1H), 8.32 - 8.30 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.81 - 7.70 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 5.30 - 5.(m, 1H), 4.89 - 4.74 (m, 2H), 4.47 - 4.39 (m, 1H), 4.31 (d, J = 11.6 Hz, 2H), 4.04 - 4.03 (m, 1H), 3.72 - 3.60 (m, 3H), 2.62 - 2.57 (m, 2H), 1.63 (d, J = 6.4 Hz, 3H), 1.(d, J = 6.4 Hz, 6H), 1.07 (d, J = 6.8 Hz, 3H) ppm 264 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 541 602.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.51 - 9.49 (m, 1H), 9.39 (s, 1H), 8.71 - 8.56 (m, 2H), 8.40 (brs, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.81 - 7.70 (m, 2H), 7.03 (d, J = 8.5 Hz, 1H), 4.79 (br d, J = 5.6 Hz, 2H), 4.31 (br d, J = 11.8 Hz, 2H), 4.18 - 4.06 (m, 1H), 3.72 - 3.63 (m, 2H), 3.61 - 3.53 (m, 2H), 2.53 - 2.52 (m, 2H), 2.35 (s, 3H), 2.32 - 2.24 (m, 1H), 2.14 (brd, J = 15.2 Hz, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 542 569.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.63 (m, 1H), 9.42 (s, 1H), 8.65 (d, J =8.8 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.45 (d,J- 7.8 Hz, 1H), 8.43 (br s, 1H), 8.27 - 8.26 (m, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.(d, J = 7.8 Hz, 1H), 4.96 (s, 2H), 4.82 (br d, J = 5.4 Hz, 2H), 4.29 - 4.28 (m, 1H), 4.09 - 3.93 (m, 4H), 3.69 - 3.59 (m, 1H), 2.05 - 2.03 (m, 3H), 1.16 (d, J = 7.2 Hz, 3H) ppm 543 587.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.72 - 9.70 (m, 1H), 9.43 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), 8.25 - 8.12 (m, 2H), 7.86 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 5.16-4.91 (m, 2H), 4.82 (brd, J = 4.6 Hz, 2H), 4.41 -4.(m, 1H), 4.12-3.93 (m, 4H), 3.79-3.67 (m, 1H), 2.06-2.04 (m, 3H), 1.21 -1.(m, 3H) ppm 544 602.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.51- 9.49 (m, 1H), 9.39 (s, 1H), 8.72 - 8.57 (m, 2H), 8.28 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.- 7.69 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 4.79 (br d, J = 5.6 Hz, 2H), 4.31 (br d, J = 11.6 Hz, 2H), 4.19 - 4.02 (m, 1H), 3.74 - 3.63 (m, 2H), 3.61 - 3.54 (m, 2H), 2.54 (s, 2H), 2.38-2.26 (m, 4H), 2.14 (brd, J = 14.6 Hz, 1H), 1.48 (d, J = 6.2 Hz, 3H), 1.(d, J = 6.2 Hz, 6H) ppm 545 546.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.57 (m, 1H), 9.08 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.33 - 8.22 (m, 3H), 7.82 - 7.70 (m, 2H), 7.(s, 1H), 7.20 (d, J = 2.0 Hz, 1H), 4.96 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.35 - 4.(m, 5H), 4.02 (d, J = 6.0 Hz, 1H), 3.70 - 3.61 (m, 1H), 2.25 (s, 3H), 1.19-1.12 (m, 3H) ppm 546 517.3 1H NMR (400 MHz, METHANOL-d4) 6 = 8.87 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.- 8.39 (m, 3H), 8.22 - 8.16 (m, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J = 9.2 Hz, 1H), 5.11 (s, 2H), 5.05 (s, 2H), 4.80 (s, 2H), 4.35 - 4.33 (m, 2H), 4.25 - 4.23 (m, 2H), 3.55 - 3.51 (m, 2H), 3.18 - 3.15 (m, 2H) ppm 547 622 1H NMR (400 MHz, METHANOL-d4) 6 = 9.30 (s, 1H), 8.70 - 8.61 (m, 2H), 8.61 - 8.56 (m, 1H), 8.48 (s, 1H), 8.34 (d, J = 2.0Hz, 1H), 8.00 - 7.88 (m, 2H), 7.75 - 7.(m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.69 - 5.64 (m, 1H), 4.92 (s, 2H), 4.41 -4.27 (m, 3H), 3.94 - 3.83 (m, 2H), 3.82 - 3.73 (m, 2H), 3.64 - 3.59 (m, 1H), 2.58 - 2.52 (m, 2H), 1.69 (d, J = 6.8 Hz, 3H), 1.29 (d, J = 6.4 Hz, 6H) ppm 265 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 548 547.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.48 (m, 1H), 9.QQ (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.29 - 8.17 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.41 - 7.31 (m, 2H), 6.60 - 6.46 (m, 2H), 4.97 (s, 2H), 4.69 (d, J = 5.Hz, 2H), 4.32 - 4.18 (m, 6H), 3.73 (s, 3H), 3.71 - 3.65 (m, 2H) ppm 549 546.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.53 - 9.51 (m, 1H), 9.09 (s, 1H), 8.43 - 8.35 (m, 1H), 8.34 - 8.22 (m, 2H), 8.16 (d, J = 1.2 Hz, 1H), 7.78 (s, 1H), 7.48 (s, 1H), 7.21 (d, J = 1.2 Hz, 1H), 5.06 (s, 2H), 4.73 (brd, J = 5.8 Hz, 2H), 4.33 (s, 4H), 4.25 - 4.(m, 2H), 3.70 - 3.63 (m, 2H), 2.50 - 2.50 (m, 3H), 2.26 (s, 3H) ppm 550 550.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.72 - 9.58 (m, 1H), 9.09 (s, 1H), 8.44 - 8.39 (m, 1H), 8.33 - 8.24 (m, 2H), 8.17 - 8.16 (m, 1H), 7.80 - 7.76 (m, 1H), 7.50 (s, 1H), 7.(d, J = 1.2 Hz, 1H), 5.03 (s, 2H), 4.74 (br d, J = 5.6 Hz, 2H), 4.38 - 4.30 (m, 4H), 4.27 - 4.19 (m, 2H), 3.80 - 3.74 (m, 2H), 2.26 (s, 3H) ppm 551 531.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.74 - 9.72 (m, 1H), 9.26 (s, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.63 (s, 1H), 8.50 - 8.43 (m, 2H), 7.75 (d, J = 9.2 Hz, 1H), 7.65 - 7.(m, 3H), 7.02 (s, 1H), 6.97 - 6.95 (m, 1H), 4.93 (d, J = 6.0 Hz, 2H), 4.54 - 4.40 (m, 6H), 3.88 - 3.84 (m, 2H), 2.50 (s, 5H) ppm 552 566 1H NMR (400 MHz, DMSO-d6) 6 = 9.68 - 9.66 (m, 1H), 9.08 (s, 1H), 8.50 (d, J =1.6 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 8.32 - 8.25 (m, 2H), 7.77 (d, J = 1.2 Hz, 1H), 7.50 (s, 1H), 7.21 (d, J = 1.4 Hz, 1H), 5.20 (s, 2H), 4.73 (brd, J = 5.6 Hz, 2H), 4.- 4.31 (m, 4H), 4.27 - 4.19 (m, 2H), 3.82 - 3.74 (m, 2H), 2.25 (s, 3H) ppm 553 622.1 1H NMR (400 MHz, METHANOL-d4) 6 = 9.31 (s, 1H), 8.69 - 8.64 (m, 2H), 8.62 - 8.56 (m, 1H), 8.50 - 8.46 (m, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.97 - 7.90 (m, 2H), 7.- 7.73 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.69 - 5.64 (m, 1H), 4.92 (s, 2H), 4.42 - 4.27 (m, 3H), 3.91 - 3.82 (m, 2H), 3.81 - 3.74 (m, 2H), 3.65 - 3.58 (m, 1H), 2.59 - 2.53 (m, 2H), 1.70 (d, J = 6.4 Hz, 3H), 1.29 (d, J = 6.4 Hz, 6H) ppm 554 564.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.62 (m, 1H), 9.08 (s, 1H), 8.39 (d, J = 1.2 Hz, 1H), 8.33-8.24 (m, 2H), 8.18 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.52 (s, 1H), 7.21 (d, J = 1.2 Hz, 1H), 5.12 - 5.02 (m, 1H), 5.00 - 4.91 (m, 1H), 4.(d, J = 5.2 Hz, 2H), 4.37 - 4.25 (m, 5H), 4.02 (d, J = 13.2 Hz, 1H), 3.80 - 3.69 (m, 1H), 2.25 (s, 3H), 1.18 (d, J = 7.2 Hz, 3H) ppm 555 587.2 1H NMR (400 MHz, METHANOL-d4) 6 = 8.90 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.- 8.19 (m, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.(d, J = 9.2 Hz, 1H), 7.11 -7.07 (m, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.33 (d, J = 8.Hz, 1H), 5.33 - 5.30 (m, 1H), 5.08 - 5.02 (m, 4H), 4.82 (s, 2H), 4.73 - 4.70 (m, 2H), 4.35 - 4.32 (m, 2H), 4.14 - 4.11 (m, 2H), 3.53 - 3.51 (m, 2H), 2.83 - 2.80 (m, 2H), 2.03 - 1.96 (m, 2H) ppm 266 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 556 530.2 1H NMR (40Q MHz, DMSO-d6) 6 = 9.59 - 9.57 (m, 1H), 9.Q7 (s, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.27- 8.25 (m, 1H), 8.19 (d, J = 9.2 Hz, 1H),8.12-8.(m, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.Hz, 1H), 7.51 (s, 1H), 7.05 - 7.03 (m, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.50 - 4.43 (m, 1H), 4.26 - 4.22 (m, 2H), 3.72 - 3.67 (m, 2H), 3.55 - 3.49 (m, 1H), 2.94 - 2.92 (m, 1H), 2.55 (brs, 1H), 2.16 - 2.06 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H) ppm 557 532.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.54 (m, 1H), 9.09 (s, 1H), 8.53 (d, J =1.8 Hz, 1H), 8.41 - 8.37 (m, 1H), 8.31 - 8.23 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.(s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.74 (br d, J = 6.0 Hz, 2H), 4.34 - 4.27 (m, 4H), 4.25 - 4.20 (m, 2H), 3.70 - 3.65 (m, 2H), 2.36 (s, 3H) ppm 558 540.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.60 - 9.51 (m, 1H), 9.05 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.38 (s, 1H), 8.28 - 8.21 (m, 2H), 7.85 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.49 - 7.41 (m, 4H), 4.97 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.24 - 4.(m, 2H), 3.99 - 3.97 (m, 2H), 3.69 - 3.65 (m, 2H), 2.81 - 2.80 (m, 2H), 1.94 - 1.(m, 2H) ppm 559 602.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.55 - 9.54 (m, 1H), 9.38 (s, 1H), 8.67 - 8.60 (m, 2H), 8.43 (s, 1H), 8.25 - 8.22 (m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.73 - 7.71 (m, 1H), 7.30 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 6.4 Hz, 1 H) 4.79 (d, J = 4.2 Hz, 2H), 4.31 (d, J = 11.6 Hz, 2H), 3.67 - 3.66 (m, 2H), 3.60 - 3.59 (m, 2H), 2.51 - 2.(m, 2H), 2.24 - 2.21 (m, 2H), 1.31 (s, 6H), 1.20 (d, J = 6.0 Hz, 2H) ppm 56Q 587.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.39 (s, 1H), 9.28 - 9.27 (m, 1H), 8.67-8.63 (m, 2H), 8.34 (d, J = 2.4 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 4.75 (brd, J = 6.Hz, 2H), 4.32 (br d, J = 11.2 Hz, 2H), 3.96 - 3.92 (m, 1H), 3.73 - 3.63 (m, 4H), 3.(s, 3H), 2.54 - 2.52 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.0 Hz, 6H) ppm 561 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.56 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.32 (s, 1H), 8.25 - 8.23 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.25 - 4.19 (m, 3H), 4.19-4.05 (m, 2H), 3.71 -3.64 (m, 2H), 3.21 (s, 3H),2.81 -2.80 (m, 2H), 1.- 1.94 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H) ppm 562 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.55 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.33 (brs, 1H), 8.25-8.24 (m, 1H), 8.18 (d, J = 9.4 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.(d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.8 Hz, 2H), 4.28 - 4.19 (m, 3H), 4.19 - 4.07 (m, 2H), 3.75 - 3.63 (m, 2H), 3.21 (s, 3H), 2.81 - 2.80 (m, 2H), 1.96 - 1.95 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H) ppm 267 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 563 566.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58-9.56 (m, 1H), 9.11 (s, 1H), 8.53 (d, J =1.8 Hz, 1H), 8.40 (s, 1H), 8.31 - 8.19 (m, 2H), 7.99 (d, J = 9.2 Hz, 1H), 7.75 - 7.(m, 2H), 7.52 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.00 - 6.64 (m, 1H), 4.98(s, 2H), 4.75 (d, J = 5.8 Hz, 2H), 4.26 - 4.20 (m, 2H), 4.20 - 4.11 (m, 2H), 3.74 -3.64 (m, 2H), 2.88 - 2.86 (m, 2H), 2.04 -1.91 (m, 2H) ppm 564 574.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.57 - 9.56 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.38 (brs, 1H), 8.26-8.24 (m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.00 (d, J = 9.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.(d, J = 7.4 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.8 Hz, 2H), 4.40 (s, 2H), 4.30 -4.(m, 2H), 4.18 - 4.09 (m, 2H), 3.73 - 3.64 (m, 2H), 3.53 - 3.51 (m, 2H), 2.81 - 2.(m, 2H), 1.95 - 1.93 (m, 2H), 1.17 - 1.15 (m, 3H) ppm 565 546.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.55 - 9.53 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.29-8.21 (m, 1H), 8.11 (d, J = 9.4 Hz, 1H), 7.97 - 7.66 (m, 3H), 7.(s, 1H), 7.32 (d, J = 3.0 Hz, 1H), 4.97 (s, 2H), 4.71 (brd, J = 5.8 Hz, 2H), 4.27 - 4.17 (m, 2H), 4.16 - 4.06 (m, 2H), 3.81 (s, 3H), 3.72 - 3.64 (m, 2H), 2.80 - 2.78 (m, 2H), 1.99 - 1.87 (m, 2H) ppm 566 571.1 1H NMR (400 MHz, METHANOL-d4) 6 = 9.12 - 9.03 (m, 1H), 8.65 - 8.59 (m, 1H), 8.35-8.15 (m, 2H), 8.10-7.91 (m, 1H), 7.73-7.61 (m, 2H), 7.55-7.39 (m, 1H), 6.18 (d, J = 8.0 Hz, 1H), 5.05 (s, 2H), 4.86 (s, 2H), 4.40 - 4.30 (m, 2H), 4.23 - 4.(m, 2H), 4.14 - 3.91 (m, 4H), 3.58 - 3.49 (m, 2H), 2.77 - 2.74 (m, 2H), 2.37 - 2.(m, 2H), 2.13 - 2.01 (m, 2H) ppm 567 587.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.39 (s, 1H), 9.28 - 9.27 (m, 1H), 8.68 - 8.61 (m, 2H), 8.35 (d, J = 2.0 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 4.77 (brd, J = 5.Hz, 2H), 4.32 (br d, J = 11.4 Hz, 2H), 3.95 - 3.92 (m, 1H), 3.76 - 3.65 (m, 4H), 3.(s, 3H), 2.54 - 2.53 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.0 Hz, 6H) ppm 568 546.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.56 (m, 1H), 9.08 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.32 (brs, 1H), 8.27-8.16 (m, 2H), 8.04 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.59 - 7.41 (m, 2H), 6.46 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.8 Hz, 2H), 4.29 - 4.18 (m, 2H), 4.17 - 4.06 (m, 2H), 3.72 - 3.65 (m, 5H), 2.75 - 2.73 (m, 2H), 1.95 - 1.93 (m, 2H) ppm 569 544.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.61 (m, 1H), 9.37 (s, 1H), 8.69 - 8.59 (m, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.28 - 8.25 (m, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 5.Hz, 2H), 4.28 - 4.18 (m, 2H), 3.74 - 3.63 (m, 2H), 3.26 - 3.22 (m, 2H), 3.11 (s, 3H), 2.83 - 2.75 (m, 2H), 1.90 - 1.78 (m, 2H), 1.76 - 1.65 (m, 2H) ppm 268 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 570 584.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.52 (m, 1H), 9.12 (s, 1H), 8.57 - 8.50 (m, 1H), 8.47 - 8.37 (m, 1H), 8.34 - 8.19 (m, 2H), 7.94 (d, J = 9.2 Hz, 1H), 7.86 - 7.(m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.75 (d, J = 6.4 Hz, 2H), 4.25 - 4.15 (m, 4H), 3.70 - 3.65 (m, 2H), 2.97 - 2.86 (m, 2H), 2.05- 1.96 (m, 2H) ppm 571 580.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.03 (s, 1H), 8.62 (d, J = 1.0 Hz, 1H), 8.- 8.44 (m, 2H), 8.19 - 8.17 (m, 2H), 8.00 (d, J = 9.2 Hz, 1H), 7.73 - 7.59 (m, 3H), 7.29 (d, J = 7.4 Hz, 1H), 5.05 (s, 2H), 4.82 - 4.80 (m, 2H), 4.39 - 4.31 (m, 2H), 4.- 4.24 (m, 2H), 3.55 - 3.50 (m, 2H), 3.00 - 2.90 (m, 2H), 2.09 - 2.07(m, 2H), 1.89 - 1.86 (m, 3H) ppm 572 533.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.57 - 9.56 (m, 1H), 9.03 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.29 - 8.14 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.41 (s, 1H), 7.31 - 7.17 (m, 2H), 6.89 - 6.86(m, 1H), 4.(s, 2H), 4.71 (d, J = 6.0 Hz, 2H), 4.26 - 4.18 (m, 2H), 3.99 - 3.97 (m, 2H), 3.72 - 3.61 (m, 2H), 2.73 - 2.71 (m, 2H), 1.95 - 1.89 (m, 2H) ppm 573 560.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.57 - 9.54 (m, 1H), 9.04 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.26-8.23 (m, 1H), 8.15 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.47 (s, 1H), 6.79 (d, J = 5.6 Hz, 1H), 4.98 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.23 - 4.21 (m, 2H), 4.18 - 4.11 (m, 4H), 3.69 - 3.66 (m, 2H), 2.68 - 2.65 (m, 2H), 1.94 - 1.88 (m, 2H), 1.38 - 1.34 (m, 3H) ppm 574 553.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.67 - 9.65 (m, 1H), 9.27 (s, 1H), 8.79 (d, J = 4.0 Hz, 1H), 8.63 (d, J = 8.8 Hz, 1H), 8.52 (s, 1H), 8.39 (s, 2H), 8.26 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H), 4.98 (s, 2H), 4.75 (d, J = 6.4 Hz, 2H), 4.23 - 4.21 (m, 2H), 3.76-3.74 (m, 4H), 3.69 - 3.66 (m, 2H), 3.31=3.29 (m, 4H) ppm 575 566.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.71 - 9.68 (m, 1H), 9.39 (s, 1H), 8.71 - 8.65 (m, 1H), 8.63 - 8.57 (m, 2H), 8.32 - 8.30 (m, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.86 - 7.(m, 2H), 7.71 - 7.67 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.81 (d, J = 6.0 Hz, 2H), 4.- 4.56 (m, 1H), 4.50 - 4.37 (m, 1H), 4.32 - 4.28 (m, 1H), 3.43 (s, 3H), 3.24 - 3.17 (m, 1H), 3.01 - 2.89 (m, 1H), 2.64 - 2.58 (m, 1H), 1.91 - 1.87 (m, 1H), 1.50 - 1.34 (m, 2H), 1.01 (d, J = 6.8 Hz, 3H) ppm 576 560.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.54 (m, 1H), 9.08 (s, 1H), 8.52 (d, J =1.6 Hz, 1H), 8.39 (s, 1H), 8.28 - 8.17 (m, 2H), 7.99 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.54 - 7.46 (m, 2H), 6.47 - 6.40 (m, 1H), 4.99 - 4.95 (m, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.25 - 4.20 (m, 2H), 4.17 - 4.07 (m, 4H), 3.70 - 3.66 (m, 2H), 2.75 - 2.72 (m, 2H), 1.99 - 1.90 (m, 2H), 1.26 - 1.22 (m, 3H) ppm 269 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 577 585.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.73- 9.70 (m, 1H), 9.40 (s, 1H), 9.14 (d, J = 2.0 Hz, 1H), 8.70 - 8.61 (m, 3H), 8.41 (brs 5 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.77 - 7.73 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.83 (br d, J = 5.6 Hz, 2H), 4.(br d, J = 11.6 Hz, 2H), 3.83 - 3.75 (m, 2H), 3.72 - 3.66 (m, 2H), 2.58 - 2.55 (m, 2H), 2.48 - 2.41 (m, 2H), 1.98 - 1.88 (m, 1H), 1.73 - 1.66 (m, 1H), 1.54 - 1.48 (m, 1H), 1.22 (d, J = 6.0 Hz, 6H), 0.75 - 0.64 (m, 1H) ppm 578 602.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.59 (m, 1H), 9.40 (s, 1H), 8.67 - 8.(m, 3H), 8.52 (s, 1H), 8.31 - 8.29 (m, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.83 - 7.81 (m, 2H), 7.74 - 7.73 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 6.4 Hz, 2H), 4.31 (d, J= 12 Hz, 2 H), 3.69 - 3.65 (m, 2H), 3.50 - 3.48 (m, 1H), 3.31 (s, 3H), 2.51 - 2.50 (m, 2H), 1.21 (d, J = 6.4 Hz, 6H), 0.64 - 0.62 (m, 2H), 0.54 - 0.49 (m, 2H) ppm 579 585.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.73 - 9.71 (m, 1H), 9.40 (s, 1H), 9.14 (d, J = 2.0 Hz, 1H), 8.70 - 8.61 (m, 3H), 8.42 (brs, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.77 - 7.73 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.83 (brd, J = 5.6 Hz, 2H), 4.(br d, J = 11.2 Hz, 2H), 3.81 - 3.75 (m, 2H), 3.73 - 3.66 (m, 2H), 2.65 - 2.56 (m, 2H), 2.43 (br s, 2H), 1.99 - 1.87 (m, 1H), 1.74 - 1.66 (m, 1H), 1.52 - 1.50 (m, 1H), 1.(d, J = 6.0 Hz, 6H), 0.75 - 0.64 (m, 1H) ppm 580 602.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.57 - 9.56 (m, 1H), 9.39 (s, 1H), 8.70 - 8.59 (m, 2H), 8.48 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 7.Hz, 1H), 7.80 - 7.70 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.(d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.2 Hz, 2H), 3.90 (d, J = 3.6 Hz, 1H), 3.68 - 3.(m, 2H), 3.64 - 3.58 (m, 2H), 2.52 (s, 2H), 2.31 - 2.22 (m, 1H), 2.19 - 2.09 (m, 1H), 1.83 - 1.73 (m, 1H), 1.73 - 1.63 (m, 1H), 1.21 (d, J = 6.4 Hz, 6H), 1.10 -1.06 (m, 3H) ppm 581 624.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.40 (s, 1H), 8.69 - 8.60 (m, 2H), 8.48 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.- 7.71 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.63-6.18 (m, 1H), 4.81 (d, J = 5.6 Hz, 2H), 4.43 - 4.26 (m, 3H), 3.81 - 3.64 (m, 4H), 2.53 - 2.(m, 2H), 2.42 - 2.35 (m, 1H), 2.28 - 2.20 (m, 1H), 1.21 (d, J = 6.0 Hz, 6H) ppm 582 624.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.70 - 9.52 (m, 1H), 9.40 (s, 1H), 8.73 - 8.58 (m, 2H), 8.48 (d, J = 2.2 Hz, 1H), 8.32 - 8.30 (m, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.83 - 7.70 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.62 - 6.16 (m, 1H), 4.81 (br d, J = 5.6 Hz, 2H), 4.43 - 4.25 (m, 3H), 3.82 - 3.62 (m, 4H), 2.52 (br s, 2H), 2.38 - 2.36 (m, 1H), 2.29 - 2.20 (m, 1H), 1.21 (d, J = 6.2 Hz, 6H) ppm 583 586.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.69- 9.57 (m, 1H), 9.16 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.44 (brs, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.31 - 8.23 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.51 (s, 2H), 4.98 (s, 2H), 4.76 (d, J = 5.6 Hz, 2H), 4.- 4.36 (m, 4H), 4.27 - 4.20 (m, 2H), 3.70 - 3.65 (m, 2H) ppm 270 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 584 602.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.58 - 9.56 (m, 1H), 9.4Q (s, 1H), 8.72 - 8.55 (m, 2H), 8.48 (brs, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.27 - 8.26 (m, 1H), 7.90 (d, J = 7.Hz, 1H), 7.81 - 7.70 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.(br d, J = 5.8 Hz, 2H), 4.31 (br d, J = 11.4 Hz, 2H), 3.94 - 3.83 (m, 1H), 3.74 - 3.(m, 4H), 2.52 (brs, 2H), 2.27-2.25 (m, 1H), 2.19-2.06 (m, 1H), 1.87- 1.62 (m, 2H), 1.21 (d, J = 6.2 Hz, 6H), 1.08 - 1.06 (m, 3H) ppm 585 584.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.63 (m, 1H), 9.47 (s, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.45 (d,J- 4.8 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.27 - 8.26 (m, 1H), 7.93 (s, 1H), 7.82 - 7.80 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 3.6 Hz, 1H), 4.99 (s, 2H), 4.86 (brd, J = 5.6 Hz, 2H), 4.54 (s, 2H), 4.- 4.21 (m, 2H), 3.72 - 3.66 (m, 2H), 3.29 (s, 3H), 0.9Q - 0.85 (m, 2H), 0.81 - 0.74 (m, 2H) ppm 586 589.1 1H NMR (400 MHz, METHANOL-d4) 6 = 8.92 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.- 8.20 (m, 1H), 8.09 (d, J = 9.4 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.(d, J = 9.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.74 - 6.(m, 1H), 5.06 (s, 2H), 4.84 (brs, 2H), 4.41 - 4.33 (m, 2H), 4.12 - 4.04 (m, 4H), 3.- 3.70 (m, 2H), 3.56 - 3.52 (m, 2H), 3.41 (s, 3H), 2.73 - 2.71 (m, 2H), 2.01 - 2.00 (m, 2H) ppm 587 608.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.40 (s, 1H), 8.70 - 8.60 (m, 2H), 8.52 (d, J = 1.8 Hz, 1H), 8.45 (s, 1H), 8.28 - 8.26 (m, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.74 - 7.72 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.82 (d, J = 5.8 Hz, 2H), 4.31 (br d, J = 11.6 Hz, 2H), 3.97 - 3.81 (m, 2H), 3.72 - 3.64 (m, 2H), 3.64 - 3.58 (m, 2H), 2.73 - 2.63 (m, 2H), 2.52 (br d, J = 2.0 Hz, 2H), 1.21 (d, J = 6.Hz, 6H) ppm 588 55Q.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.56 (m, 1H), 9.09 (s, 1H), 8.53 (d, J = 2.Q Hz, 1H), 8.34 (s, 1H), 8.26 - 8.24 (m, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.50 (s, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.23 - 4.21 (m, 2H), 4.16 - 4.08 (m, 2H), 3.73 - 3.66 (m, 2H), 2.85 - 2.82 (m, 2H), 2.01 -1.92 (m, 2H) ppm 589 586.3 1H NMR (400 MHz, CHLOROFORM-d) 6 = 8.99 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.20-8.17 (m, 1H), 8.08 - 8.01 (m, 1H), 7.97 7.90 ־ (m, 1H), 7.74 (brs, 1H), 7.(s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 5.04 (s, 2H), 4.92 (d, J = 5.2 Hz, 2H), 4.42 - 4.36 (m, 2H), 4.28 - 4.25 (m, 2H), 3.(d, J = 6.8 Hz, 2H), 3.46 - 3.36 (m, 2H), 2.81 - 2.78 (m, 2H), 2.10 - 2.03 (m, 2H), 1.25-1.17 (m, 1H), 0.61 - Q.53 (m, 2H), 0.31 - 0.24 (m, 2H) ppm 271 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 590 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.63 (m, 1H), 9.27 (br s, 1H), 8.59 - 8.(m, 1H), 8.33 - 8.21 (m, 2H), 8.14 (brd, J = 9.0 Hz, 1H), 7.78 - 7.68 (m, 2H), 7.(s, 1H), 4.98 (s, 2H), 4.82 (brd, J = 4.6 Hz, 2H), 4.41 (s, 2H), 4.30 - 4.14 (m, 4H), 3.70 - 3.66 (m, 2H), 3.34 (br s, 3H), 2.81 - 2.80 (m, 2H), 2.38 (s, 3H), 2.01 - 1.(m, 2H) ppm 591 534.2 1H NMR (400 MHz, CHLOROFORM-d) 6 = 8.99 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.20 - 8.17 (m, 1H), 8.05 (d, J = 2.8 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.75 (s, 1H), 7.(s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 5.04 (s, 2H), 4.93 (d, J = 5.2 Hz, 2H), 4.43 - 4.(m, 2H), 4.33 - 4.27 (m, 2H), 3.45 - 3.38 (m, 2H), 2.91 - 2.88 (m, 2H), 2.13 - 2.(m, 2H) ppm 592 559.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.64 (m, 1H), 9.47 (s, 1H), 8.80 (d, J = 8.8 Hz, 1H), 8.66 (d, J = 8.8 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.29 - 8.24 (m, 2H), 8.14 - 7.69 (m, 3H), 7.34 - 7.31 (m, 1H), 4.97 (s, 2H), 4.84 (d, J = 5.6 Hz, 2H), 4.- 4.27 (m, 1H), 4.04 - 3.99 (m, 1H), 3.72 - 3.58 (m,1H),1.17(d,J- 7.2 Hz, 3H) ppm 593 545.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.68 - 9.66 (m, 1H), 9.25 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.33 - 8.24 (m, 2H), 8.20 - 8.11 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.(s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.38 - 4.30 (m, 2H), 4.24 - 4.21 (m, 2H), 3.71 - 3.65 (m, 2H), 3.38 - 3.36 (m, 2H), 2.91 (s, 3H), 2.32 (s, 3H) ppm 594 568.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.70 - 9.60 (m, 1H), 9.33 - 9.24 (m, 1H), 8.(d, J = 1.7 Hz, 1H), 8.47 - 8.39 (m, 2H), 8.26 (brd, J = 8.0 Hz, 1H), 7.74 (d, J = 8.Hz, 1H), 7.70 - 7.63 (m, 1H), 7.51 (br d, J = 8.2 Hz, 1H), 7.39 (br d, J = 8.0 Hz, 1H), 7.06 - 6.72 (m, 1H), 4.98 (s, 2H), 4.80 (brs, 2H), 4.43 (s, 4H), 4.23 - 4.21 (m, 2H), 3.70 - 3.65 (m, 2H) ppm 595 559.3 1H NMR (400 MHz, METHANOL-d4) 5 = 9.18 (s, 1H), 8.64 (d, J = 1.6 Hz, 1H), 8.- 8.38 (m, 1H), 8.29 - 8.17 (m, 1H), 8.08 - 7.91 (m, 1H), 7.75 - 7.55 (m, 3H), 6.57 (br d, J = 8.8 Hz, 1H), 5.06 (s, 2H), 4.89 (s, 2H), 4.40 - 4.31 (m, 2H), 4.28 - 4.19 (m, 2H), 3.61 - 3.51 (m, 2H), 3.21 - 3.08 (m, 6H), 2.86 - 2.75 (m, 2H), 2.22 - 2.07 (m, 2H) ppm 596 573.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.76 - 9.73 (m, 1H), 9.40 (s, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.68 - 8.61 (m, 2H), 7.92 -7.90 (m, 1H), 7.(s, 1H), 7.76 -7.73 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.82 (d, J = 5.6 Hz, 2H), 4.(d, J = 11.2 Hz, 2H), 3.69 - 3.65 (m, 3H), 3.24 - 3.22 (m, 2H), 2.52 - 2.50 (m, 2H), 2.38-2.35 (m, 1H), 2.22 - 2.19 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H), 1.21 (d,J=6.Hz, 6H) ppm 272 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 597 573.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.76 - 9.73 (m, 1H), 9.40 (s, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.67 - 8.61 (m, 2H), 7.93 -7.90 (m, 1H), 7.(s, 1H), 7.76 -7.73 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.83 (d, J = 5.6 Hz, 2H), 4.(d, J = 11.2 Hz, 2H), 3.69 - 3.65 (m, 3H), 3.24 - 3.22 (m, 2H), 2.52 - 2.50 (m, 2H), 2.37-2.35 (m, 1H), 2.22 - 2.19 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.Hz, 6H) ppm 598 586.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.60 - 9.57 (m, 1H), 9.06 (s, 1H),8.53 (s, 1H), 8.26 - 8.24(m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.73 (d, J= 5.6 Hz, 2H), 4.44 (s, 2H), 4.23 - 4.21 (m, 2H), 4.15 - 4.12 (m, 2H), 3.69 - 3.67 (m, 2H), 3.41 - 3.39 (m, 1H), 2.81 - 2.78 (m, 2H), 1.96 - 1.93 (m, 2H), 0.57 - 0.53 (m, 2H), 0.46 - 0.45 (m, 2H) ppm 599 594.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.58 -9.56 (m, 1H), 9.09 (s, 1H), 8.53 (d, J = 1.Hz, 1H), 8.28 - 8.19 (m, 2H), 8.00 (d, J = 9.2 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.50 (s, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.8 Hz, 2H), 4.44 (s, 2H), 4.26 - 4.19 (m, 2H), 4.17 - 4.09 (m, 2H), 3.73 - 3.62 (m, 2H), 3.30 (s, 3H), 2.84 -2.82 (m, 2H), 2.01 -1.87 (m, 2H) ppm 600 542.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.52 (m, 1H), 9.07 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.47 (s, 1H), 8.25 - 8.23 (m, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.05 - 8.(m, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.24 - 7.(m, 1H), 7.01 - 6.99 (m, 1H), 4.98 (s, 2H), 4.73 (br d, J = 6.0 Hz, 2H), 4.32 - 4.(m, 4H), 3.73- 3.62 (m, 2H), 1.91 -1.81 (m, 2H), 1.13-1.01 (m, 2H), 1.00-0.(m, 2H) ppm 601 596.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59- 9.56 (m, 1H), 9.11 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 8.27 - 8.20 (m, 2H), 7.98 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.48 - 6.14 (m, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.42-4.33 (m, 2H), 4.26-4.(m, 2H), 4.14 - 4.07 (m, 2H), 3.71 - 3.64 (m, 2H), 2.78 - 2.75 (m, 2H), 2.01 - 1.(m, 2H) ppm 602 560.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.51 (m, 1H), 9.05 - 8.94 (m, 1H), 8.53 (s, 1H), 8.43 (brs, 1H), 8.26 (brd, J = 7.2 Hz, 1H), 8.10 (brd, J = 9.2 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.73 (brd, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 4.98 (s, 2H), 4.82 - 4.59 (m, 2H), 4.30 - 4.17 (m, 2H), 4.11 - 4.10 (m, 2H), 3.81 (s, 3H), 3.69 (br d, J = 3.8 Hz, 2H), 2.79 - 2.77 (m, 2H), 2.28 (s, 3H), 1.96 - 1.88 (m, 2H) ppm 603 534.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.56 (m, 1H), 9.12 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.43 (brs, 1H), 8.31 - 8.23 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.52 (s, 1H), 6.72 - 6.70 (m, 1H), 4.98 (s, 2H), 4.75 (d, J = 5.6 Hz, 2H), 4.26 - 4.19 (m, 2H), 4.15 - 4.09 (m, 2H), 3.70 - 3.65 (m, 2H), 2.82 2.80 (m, 2H), 2.01 -1.91 (m, 2H) ppm 273 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 604 572.1 1H NMR (40Q MHz, DMSO-d6) 6 = 9.65 - 9.63 (m, 1H), 9.39 (s, 1H), 8.69 - 8.59 (m, 2H), 8.55 (d, J = 1.6 Hz, 1H), 8.28 - 8..25 (m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.68 (m, 2H), 6.57 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H), 4.82 (br d, J = 5.Hz, 2H), 4.72 - 4.72 (m, 2H), 4.36 - 4.33 (m, 2H), 4.26 - 4.17 (m, 4H), 3.82 - 3.(m, 2H), 3.74 - 3.67 (m, 2H), 3.31 - 3.28 (m, 1H), 3.16 - 3.08 (m, 1H) ppm 605 559.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.48 (m, 1H), 8.98 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 8.28 - 8.21 (m, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.42- 7.35 (m, 2H), 7.30 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.05-6.(m, 1H), 4.98 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.35 (s, 2H), 4.26 - 4.19 (m, 2H), 4.04 - 3.95 (m, 2H), 3.73 - 3.65 (m, 2H), 3.25 (s, 3H), 2.76 - 2.69 (m, 2H), 1.96 - 1.87 (m, 2H) ppm 606 557.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.58 - 9.55 (m, 1H), 9.03 (s, 1H), 8.52 (d, J =1.6 Hz, 1H), 8.45 - 8.42 (m, 1H), 8.29 - 8.22 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.(d, J = 9.2 Hz, 1H), 7.39 (s, 1H), 7.19 (d, J = 2.0 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.80- 6.72 (m, 1H), 4.97 (s, 2H), 4.71 (d, J = 6.0 Hz, 2H), 4.25 - 4.17 (m, 6H), 3.69 - 3.(m, 2H), 1.88 - 1.81 (m, 1H), 0.88 - 0.81 (m, 2H), 0.59 - 0.53 (m, 2H) ppm 607 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 (s, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 2.Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.48 (s, 1H), 4.98 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.34 - 4.32 (m, 1H), 4.26 - 4.(m, 2H), 4.17 - 4.10 (m, 2H), 3.72 - 3.65 (m, 2H), 3.15 (s, 3H), 2.86 - 2.83 (m, 2H), 2.01 - 1.92 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H) ppm 608 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.57 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J = 7.6 Hz,1 H), 8.17 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 2.Hz, 1H), 7.48 (s, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.34 - 4.32 (m, 1H), 4.28 - 4.20 (m, 2H), 4.18 - 4.10 (m, 2H), 3.73 - 3.65 (m, 2H), 3.15 (s, 3H), 2.86 - 2.84 (m, 2H), 2.00 - 1.96 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H) ppm 609 605.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.65 (m, 1H), 9.43 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.39 (br s, 1H), 8.28 - 8.26 (m, 1H), 8.02 - 8.00 (m, 1H), 7.82 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.29 - 7.(m, 1H), 7.22 - 7.16 (m, 1H), 4.96 (s, 2H), 4.82 (brd, J = 5.4 Hz, 2H), 4.28 - 4.(m, 1H), 4.01 - 4.00 (m, 1H), 3.82 - 3.74 (m, 2H), 3.68 - 3.61 (m, 1H), 3.31 (br d, J = 11.2 Hz, 2H), 2.43 2.41 (m, 2H), 1.17-1.12 (m, 9H) ppm 274 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 610 606.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.64 (m, 1H), 9.47 (s, 1H), 8.73 (d, J = 8.6 Hz, 1H), 8.51 (d, J = 1.2 Hz, 1H), 8.41 (br s, 1H), 8.27- 8.25 (m, 1H), 8.14 (d, J = 5.0 Hz, 1H), 8.08 - 8.06 (m, 1H), 7.86 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.34 - 7.(m, 1H), 4.96 (s, 2H), 4.83 (brd, J = 5.4 Hz, 2H), 4.28 -4.26 (m, 1H), 4.01 - 3.99 (m, 1H), 3.88 (brd, J = 12.4 Hz, 2H), 3.78 - 3.69 (m, 2H), 3.67 - 3.60 (m, 1H), 2.60 - 2.58 (m, 2H), 1.18-1.11 (m, 9H) ppm 611 544.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.67 - 9.59 (m, 1H), 9.36 (s, 1H), 8.63 (s, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.30 - 8.23 (m, 1H), 7.81 - 7.70 (m, 3H), 7.(d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 6.0 Hz, 2H), 4.25 - 4.21 (m, 2H), 3.71 - 3.66 (m, 2H), 3.42 (brd, J = 5.6 Hz, 2H), 3.21 (s, 3H), 3.00 - 2.86 (m, 1H), 2.03 - 1.91 (m, 1H), 1.73 - 1.61 (m, 1H), 1.25 (d, J = 6.9 Hz, 3H) ppm 612 544.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.63 - 9.61 (m, 1H), 9.35 (s, 1H), 8.62 (s, 2H), 8.53 (d. J = 1.8 Hz, 1H), 8.39 (br s, 1H), 8.26 - 8.24 (m, 1H), 7.80 - 7.68 (m, 3H), 7.33 (d, J = 7.4 Hz, 1H), 4.97 (s, 2H), 4.80 (d, J = 5.8 Hz, 2H), 4.27 - 4.17 (m, 2H), 3.72 - 3.63 (m, 2H), 3.41 - 3.38 (m, 1H), 3.19 (s, 3H), 3.08 - 3.06 (m, 1H), 2.89 - 2.74 (m, 1H), 2.46-2.41 (m, 1H), 2.14-2.00 (m, 1H), 1.02 (d, J = 6.6 Hz, 3H) ppm 613 575.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.63 - 9.60 (m, 1H), 9.37 (s, 1H), 8.57 - 8.47 (m, 2H), 8.25 - 8.23 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.09 - 6.(m, 2H), 6.92 - 6.83 (m, 1H), 4.97 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.31 - 4.17 (m, 3H), 4.12 - 4.08 (m, 1H), 3.82 - 3.74 (m, 1H), 3.71 - 3.64 (m, 2H), 3.44 - 3.38 (m, 2H), 3.30 (s, 3H), 2.94 (s, 3H) ppm 614 575.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.63 - 9.60 (m, 1H), 9.37 (s, 1H), 8.58 - 8.47 (m, 2H), 8.25 - 8.23 (m, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.79 - 7.69 (m, 2H), 7.09 - 6.(m, 2H), 6.88 - 6.85 (m, 1H), 4.97 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.30 - 4.19 (m, 3H), 4.12 - 4.08 (m, 1H), 3.84 - 3.73 (m, 1H), 3.71 - 3.63 (m, 2H), 3.44 - 3.38 (m, 2H), 3.30 (s, 3H), 2.94 (s, 3H) ppm 615 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.54 (m, 1H), 9.03 (s, 1H), 9.12 - 8.93 (m, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.26 - 8.24 (m, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H). 7.73 (d, J = 8.0 Hz, 1H), 7.55- 7.54 (m, 1H), 7.46 (s, 1H), 7.11 - 7.09 (m, 1H), 7.00 - 6.97 (m, 1H), 4.98 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.26 - 4.(m, 4H), 3.76 - 3.62 (m, 2H), 3.43 - 3.37 (m, 4H), 1.13 -1.05 (m, 3H) ppm 616 558.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.55 (m, 1H), 9.10 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.46 (s, 2H), 8.30 (d, J = 8.8 Hz, 1H), 8.25 - 8.23 (m, 1H), 8.22 - 8.(m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.31 - 4.27 (m, 4H), 4.25 - 4.(m, 2H), 3.70 - 3.65 (m, 2H), 2.04 - 1.97 (m, 1H), 0.89 - 0.84 (m, 2H), 0.81 - 0.(m, 2H) ppm 275 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 617 582.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.59 (m, 1H), 9.14 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.37 (d, J = 9.4 Hz, 2H), 8.30 - 8.23 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 4.98 (s, 2H), 4.75 (d, J = 5.6 Hz, 2H), 4.44 - 4.38 (m, 2H), 4.36 (br d, J = 4.8 Hz, 2H), 4.25 -4.19 (m, 2H), 3.71 - 3.65 (m, 2H), 1.96 - 1.94 (m, 3H) ppm 618 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.56 (m, 1H), 9.02 (s, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.53 - 7.38 (m, 2H), 6.92 (d, J = 1.6 Hz, 1H), 4.99 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.27 - 4.25 (m, 4H), 3.73 - 3.64 (m, 2H), 3.39 - 3.38 (m, 2H), 2.93 (s, 3H), 2.24 (s, 3H) ppm 619 548.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.55 (m, 1H), 9.06 (s, 1H), 8.53 (s, 1H), 8.40 (d, J = 4.0 Hz, 1H), 8.31 - 8.16 (m, 3H), 7.79 - 7.68 (m, 2H), 7.46 (s, 1H), 7.(d, J = 2.4 Hz, 1H), 4.98 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.33 (s, 4H), 4.26 - 4.(m, 2H), 3.81 (s, 3H), 3.70 - 3.65 (m, 2H) ppm 620 582.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.03 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.- 8.37 (m, 1H), 8.23 - 8.14 (m, 2H), 8.07 (d, J = 5.7 Hz, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.31 - 6.90 (m, 1H), 6.88 (d, J = 5.6 Hz, 1H), 5.04 (s, 2H), 4.85 - 4.85 (m, 2H), 4.39 - 4.31 (m, 2H), 4.23 - 4.21 (m, 2H), 3.56 - 3.47 (m, 2H), 2.86 (t, J = 6.7 Hz, 2H), 2.09 - 2.00 (m, 2H) ppm 621 586.3 1H NMR (400 MHz, Methanol-d4) 6 9.30 (s, 1H), 8.69 - 8.57 (m, 3H), 8.25 - 8.(m, 1H), 7.96 (s, 2H), 7.88 (d, J = 7.3 Hz, 1H), 7.74 - 7.60 (m, 2H), 6.98 (d, J = 8.Hz, 1H), 5.05 (s, 3H), 4.93 (d, J = 3.1 Hz, 3H), 4.61 (t, J = 7.8 Hz, 2H), 4.38 - 4.(m, 3H), 3.83 - 3.67 (m, 3H), 3.53 (dd, J = 5.7, 4.0 Hz, 3H), 2.52 (t, J = 7.8 Hz, 2H), 2.06-1.95 (m, 6H), 1.15 (d, J = 6.1 Hz, 3H). 622 588.3 1H NMR (400 MHz, Meihanol-d4) 6 9.30 (s, 1H), 8.69 - 8.57 (m, 3H), 8.25 - 8.(m, 1H), 7.96 (s, 2H), 7.88 (d, J = 7.3 Hz, 1H), 7.74 - 7.60 (m, 2H), 6.98 (d, J = 8.Hz, 1H), 5.05 (s, 3H), 4.93 (d, J = 3.1 Hz, 3H), 4.61 (t, J = 7.8 Hz, 2H), 4.38 - 4.(m, 3H), 3.83 - 3.67 (m, 3H), 3.53 (dd, J = 5.7, 4.0 Hz, 3H), 2.52 (t, J = 7.8 Hz, 2H), 2.06 - 1.95 (m, 6H), 1.15 (d, J = 6.1 Hz, 3H). 623 587.3 1H NMR (400 MHz, DMSO-d6) 6 9.58 (t, J = 5.8 Hz, 1H), 9.35 (s, 1H), 8.64 (d, J = 1.7 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.38 (dd, J = 8.6, 1.7 Hz, 1H), 8.31 (dd, J = 7.8, 1.9 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.73 (dd, J = 8.5, 7.5 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.00 (s, 2H), 4.84 - 4.78 (m, 2H), 4.39 - 4.29 (m, 3H), 4.06 (dd, J = 13.3, 5.8 Hz, 1H), 3.68 (dddd, J = 14.0, 7.8, 5.9, 2.3 Hz, 3H), 2.54-2.46 (m, 1H), 1.24 (d, J = 6.2 Hz, 6H), 1.20 (d, J = 7.0 Hz, 3H). 276 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 624 605.3 1H NMR (600 MHz, DMSO-d6) 6 9.65 (t, J = 5.8 Hz, 1H), 9.32 (s, 1H), 8.62 (d, J = 1.7 Hz, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.35 (dd, J = 8.5, 1.7 Hz, 1H), 8.20 (dd, J = 9.1,3.3 Hz, 2H), 7.89 (s, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.(d, J = 8.5 Hz, 1H), 5.08 (d, J = 14.4 Hz, 1H), 4.96 (d, J = 14.4 Hz, 1H), 4.83-4.(m, 2H), 4.31 (ddd, J = 13.1, 10.1,2.4 Hz, 3H), 4.04 (dd, J = 13.3, 5.8 Hz, 1H), 3.-3.67(m, 1H), 3.69-3.63 (m, 1H), 2.50-2.45 (m, 1H), 1.28-1.23 (m, 1H), 1.(d, J = 6.2 Hz, 6H), 1.18 (d, J = 7.0 Hz, 3H). 625 551.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.58 - 9.56 (m, 1H), 9.02 (s, 1H), 8.51 (d, J =1.6 Hz, 1H), 8.40 (s, 1H), 8.29 - 8.17 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.50 (d, J =7.6 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.33 (d, J = 9.2 Hz, 1H), 4.97 (s, 2H), 4.70 (d, J =5.6 Hz, 2H), 4.27 - 4.18 (m, 2H), 3.98 - 3.94 (m, 2H), 3.70 - 3.64 (m, 2H), 2.72 -2.69(m, 2H), 1.94 - 1.88 (m, 2H) ppm 626 574.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.56 - 9.55 (m, 1H), 9.07 - 8.97 (m, 1H), 8.(d, J = 1.8 Hz, 1H), 8.28-8.21 (m, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.99 (d, J = 9.Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 9.6 Hz, 2H), 4.97 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.38 (s, 2H), 4.25 - 4.18 (m, 2H), 4.15 - 4.08 (m, 2H), 3.71 - 3.64 (m, 2H), 3.27 (s, 3H), 2.78 (t, J = 6.3 Hz, 2H), 2.27 (s, 3H), 1.93 - 1.91 (m, 2H) ppm 627 588.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.56 - 9.55 (m, 1H), 9.41 (s, 1H), 8.72 - 8.60 (m, 2H), 8.55 (d, J = 1.6 Hz, 1H), 8.45 (brs, 1H), 8.28- 8.27 (m, 1H), 7.93 (d, J = 7.Hz, 1H), 7.82 (s, 1H), 7.78 - 7.66 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 4.82 (brd, J = 5.6 Hz, 2H), 4.32 (brd, J = 12.2 Hz, 2H), 4.05 - 3.95 (m, 2H), 3.78 - 3.76 (m, 2H), 3.72 - 3.63 (m, 2H), 3.57 - 3.46 (m, 4H), 2.63 - 2.54 (m, 2H), 1.22 - 1.20 (d, J = 6.Hz, 6H) ppm 628 588.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.62 (m, 1H), 9.40 (s, 1H), 8.73 - 8.56 (m, 3H), 8.30 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.78 - 7.72 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.88 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.31 (d, J =11.6 Hz, 2H), 3.68 (d, J = 10.4 Hz, 2H), 3.62 - 3.60 (m, 2H), 3.55 - 3.48 (m, 2H), 2.53 (s, 2H), 2.29 - 2.26 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H) ppm 629 560.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 5.55 (m, 1H), 9.04 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.26 - 8.24 (m, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 4.98 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.27 4.17 ־ (m, 2H), 4.14 - 4.08 (m, 2H), 3.79 (s, 3H), 3.71 - 3.64 (m, 2H), 2.- 2.76 (m, 2H), 2.19 (s, 3H), 2.00 - 1.86 (m, 2H) ppm 277 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 630 586.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.56 (m, 1H), 9.Q7 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.42 (s, 1H), 8.25 -8.24 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.56 - 7.46 (m, 2H), 6.96 (d, J =7.6 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.27 - 4.18 (m, 2H), 4.16-4.(m, 2H), 4.02 (t, J = 7.8 Hz, 1H), 3.85 - 3.72 (m, 2H), 3.71 - 3.61 (m, 3H), 3.44 - 3.42 (m, 1H), 2.79 -2.77 (m, 2H), 2.23 - 2.15 (m, 1H), 2.10 - 2.03 (m, 1H), 1.95- 1.93 (m, 2H) ppm 631 628.4 1H NMR (400 MHz, DMSO-d6) 5 = 9.68 -9.67 (m, 1H), 9.41 (s, 1H), 8.71 - 8.60 (m, 2H), 8.43 (d, J = 1.6 Hz, 1H), 8.16 (s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.74 - 7.72 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.00 (s, 2H), 4.83 (d, J = 5.8 Hz, 2H), 4.37 - 4.26 (m, 2H), 4.24 - 4.14 (m, 2H), 3.95 - 3.83 (m, 1H), 3.72 - 3.63 (m, 4H), 2.56 - 2.54 (m, 2H), 2.37 (brs, 1H), 2.28 - 2.19 (m, 2H), 2.07 - 1.99 (m, 1H), 1.86 - 1.76 (m, 1H), 1.21 (d, J = 6.2 Hz, 6H) ppm 632 570.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.57 - 9.54 (m, 1H), 9.04 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.25-8.24 (m, 1H),8.15(d,J=9.2 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 4.97 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.28 - 4.19 (m, 2H), 4.12 - 4.05 (m, 2H), 3.74 - 3.62 (m, 2H), 2.74 - 2.71 (m, 2H), 2.33 (s, 3H), 2.12 - 2.04 (m, 1H), 1.92 - 1.89 (m, 2H), 0.88 - 0.76 (m, 4H) ppm 633 546.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.58 - 9.55 (m, 1H), 9.07 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.26-8.24 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.19 - 8.14 (m, 1H), 7.(d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.51 (s, 1H), 7.08 - 7.06 (m, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.60 - 4.52 (m, 1H), 4.- 4.19 (m, 2H), 3.99 - 3.90 (m, 2H), 3.73 - 3.62 (m, 2H), 3.17 (s, 3H), 3.08 - 3.06 (m, 1H), 2.96 - 2.88 (m, 1H) ppm 634 567.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.59 - 9.57 (m, 1H), 9.07 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.25 - 8.23 (m, 1H), 7.76 - 7.70 (m, 2H), 7.(d, J = 9.2 Hz, 1H), 7.43 (s, 1H), 7.27 - 7.22 (m, 1H), 7.08 - 6.79 (m, 2H), 4.97 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.37 - 4.31 (m, 2H), 4.26 - 4.19 (m, 4H), 3.71 - 3.(m, 2H) ppm 635 588.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.56 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.25 - 8.23 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.14 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.48 (s,1H), 7.05 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.32 - 4.31 (m, 1H), 4.23 - 4.21 (m, 2H), 4.21 - 4.05 (m, 2H), 3.71 - 3.63 (m, 2H), 3.47 - 3.35 (m, 2H), 2.81 - 2.80 (m, 2H), 2.03 - 1.86 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H), 1.12 -1.10 (m, 3H) ppm 278 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 636 588.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 -9.56 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.Hz, 1H), 8.38 (s, 1H), 8.25 - 8.23 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 9.Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.48 (s,1H), 7.05 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.8 Hz, 2H), 4.32 - 4.30 (m, 1H), 4.27 - 4.20 (m, 2H), 4.20 - 4.03 (m, 2H), 3.76 - 3.63 (m, 2H), 3.46 - 3.39 (m, 2H), 2.81 - 2.80 (m, 2H), 2.03 - 1.87 (m, 2H), 1.34 (d, J = 6.4 Hz, 3H), 1.12 - 1.(m, 3H) ppm 637 560.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.54 (m, 1H), 8.99 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.26 - 8.24 (m, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.90 (s, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.43 (s, 1H), 4.98 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.29 - 4.18 (m, 2H), 4.15 - 4.06 (m, 2H), 3.87 (s, 3H), 3.71 - 3.65 (m, 2H), 2.- 2.71 (m, 2H), 2.13 (s, 3H), 1.98 - 1.89 (m, 2H) ppm 638 575.3 1H NMR (400 MHz, CHLOROFORM-d) 6 = 9.26 (s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.22 - 8.19 (m, 1H), 8.15 - 8.07 (m, 2H), 7.92 (s, 1H), 7.(d, J = 7.6 Hz, 1H), 7.20-7.17 (m, 1H), 7.04 - 7.01 (m, 1H), 6.76 - 6.73 (m, 1H), 5.05 - 5.01 (m, 4H), 4.43 - 4.37 (m, 3H), 4.19 - 3.99 (m, 1H), 3.55 - 3.48 (m, 3H), 3.43 - 3.40 (m, 2H), 3.38 (s, 3H), 3.06 (s, 3H) ppm 639 575.3 1H NMR (400 MHz, CHLOROFORM-d) 6 = 9.25 (s, 1H), 8.55 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.21 - 8.19 (m, 1H), 8.09 - 8.04 (m, 2H), 7.80 (s, 1H), 7.(d, J = 7.6 Hz, 1H), 7.20-7.17 (m, 1H), 7.04 - 7.01 (m, 1H), 6.76 - 6.73 (m, 1H), 5.05 - 4.98 (m, 4H), 4.42 - 4.37 (m, 3H), 4.12 - 3.99 (m, 1H), 3.56 - 3.48 (m, 3H), 3.43 - 3.40 (m, 2H), 3.38 (s, 3H), 3.06 (s, 3H) ppm 64Q 521.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.49 - 9.48 (m, 1H), 8.84 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.32-8.17 (m, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.37 - 7.14 (m, 2H), 5.05 - 4.91 (m, 2H), 4.69 - 4.61 (m, 2H), 4.26 - 4.16 (m, 2H), 3.73 - 3.62 (m, 2H), 3.02 - 2.77 (m, 1H), 2.46 - 2.42 (m, 2H), 1.87 - 1.54 (m, 7H), 1.49 - 1.26 (m, 6H) ppm 641 605.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.42 - 9.36 (m, 2H), 8.67-8.63 (m, 2H), 8.23 (d, J = 1.6 Hz, 1H). 7.97 - 7.90 (m, 2H), 7.79 - 7.70 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 4.77 (br d, J = 5.6 Hz, 2H), 4.32 (br d, J = 12 Hz, 2H), 3.87 - 3.84 (m, 1H), 3.79 - 3.63 (m, 4H), 3.25 (d, J = 5.6 Hz, 3H), 2.54 - 2.52 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.0 Hz, 6H) ppm 642 605.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.42 - 9.36 (m, 2H), 8.67-8.63 (m, 2H), 8.22 (d, J = 1.6 Hz, 1H), 7.97 - 7.90 (m, 2H), 7.79 - 7.70 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 4.77 (brd, J = 5.6 Hz, 2H), 4.31 (br d, J = 12 Hz, 2H), 3.86 - 3.84 (m, 1H), 3.79 - 3.63 (m, 4H), 3.25 (d, J = 5.6 Hz, 3H), 2.55 - 2.52 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.0 Hz, 6H) ppm 279 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 643 582.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.05 (s, 1H), 8.61 (d, J = 1.6 Hz, 1H), 8.- 8.39 (m, 1H), 8.26 - 8.16 (m, 2H), 7.96 (d, J = 9.2 Hz, 1H), 7.71 - 7.59 (m, 3H), 7.45 - 7.04 (m, 1H), 6.56 (d, J = 7.8 Hz, 1H), 5.04 (s, 2H), 4.85 - 4.84 (m, 2H), 4.- 4.30 (m, 2H), 4.24 - 4.17 (m, 2H), 3.57 - 3.49 (m, 2H), 2.87 (br t,J= 6.6 Hz, 2H), 2.12 - 2.01 (m, 2H) ppm 644 571.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.58 - 9.55 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 8.25 - 8.23 (m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.38 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.75 - 6.73 (m, 1H), 4.98 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.28 - 4.19 (m, 2H), 3.99 - 3.95 (m, 2H), 3.76 - 3.71 (m, 1H), 3.70 - 3.65 (m, 2H), 2.67 - 2.64 (m, 2H), 1.93 - 1.86 (m, 2H), 0.73 - 0.57 (m, 4H) ppm 645 551.8 1H NMR (400 MHz, DMSO-d6) 5 = 9.59 (s, 1H), 9.13 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.35 - 8.31 (m, 1H), 8.27 - 8.20 (m, 2H), 7.95 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.52 (s, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.36 - 4.34 (m, 4H), 4.23 - 4.21 (m, 2H), 3.72 - 3.65 (m, 2H) ppm 646 565.8 1H NMR (400 MHz, DMSO-d6) 0 = 9.59 (s, 1H), 9.13 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.35 - 8.31 (m, 1H), 8.27 - 8.26 (z, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.24 - 8.21 (m, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.57 - 7.(m, 2H), 4.96 (s, 2H), 4.74 (brd, J = 5.6 Hz, 2H), 4.41 - 4.32 (m, 4H), 4.29 - 4.(m, 1H), 4.03 (s, 1H), 3.69 - 3.61 (m, 1H), 1.16 (d, J = 7.0 Hz, 3H) ppm 647 531.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.54 - 9.53 (m, 1H), 9.02 (s, 1H), 8.52 (d, J =2.0 Hz, 1H), 8.41 - 8.28 (m, 2H), 8.24 - 8.23 (m, 1H), 8.19 (s, 1H), 7.73 (d, J = 7.Hz, 1H), 7.51 (s, 1H), 7.31 - 7.14 (m, 2H), 6.67 (d, J = 8.2 Hz, 1H), 4.98(s, 2H), 4.72 (d, J = 5.8 Hz, 2H), 4.29 - 4.19 (m, 4H), 3.81 (s, 3H), 3.70 - 3.65 (m, 2H), 3.11 -3.09 (m, 2H) ppm 648 592.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.41 (s, 1H), 9.35 - 9.33 (m, 1H), 8.69 - 8.62 (m, 2H), 8.25 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.80 - 7.69 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 4.95 (s, 2H), 4.82 (brd, J = 6.0 Hz, 2H), 4.32 (brd, J = 11.6 Hz, 2H), 4.26 -4.18 (m, 2H), 3.73 - 3.62 (m, 4H), 2.54 - 2.53 (m, 2H), 1.(d, J = 6.4 Hz, 6H) ppm 649 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.55 (m, 1H), 9.03 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.27- 8.25 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 3.6 Hz, 1H), 7.45 (s, 1H), 7.03 - 6.98 (m, 2H), 4.98 (s, 2H), 4.78 (d, J = 13.2 Hz, 1H), 4.72 (d, J = 6.0 Hz, 2H), 4.30 - 4.18 (m, 2H), 3.69 - 3.67 (m, 3H), 3.59 (d, J = 3.2 Hz, 1H), 2.91 (s, 3H), 1.00 (d, J = 6.4 Hz, 3H) ppm 280 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 650 573.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 - 9.54 (m, 1H), 8.96 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.19 (s,1H), 8.06 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.42 (s, 1H), 7.09 (d, J = 2.8 Hz, 1H), 4.96 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.29 (d, J = 13.2 Hz, 1H), 4.13 - 4.07 (m, 2H), 4.02 - 4.00 (m, 1H), 3.70 - 3.60 (m, 1H), 2.90 (s, 6H), 2.77 - 2.75 (m, 2H), 1.97 - 1.86 (m, 2H), 1.16 (d, J = 7.2 Hz, 3H) ppm 651 574.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.47 (m, 1H), 9.12 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.32 (s, 1H), 8.25 - 8.23 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.55 - 7.40 (m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 5.04 - 4.91 (m, 2H), 4.73 (br d, J = 5.6 Hz, 2H), 4.27 - 4.09 (m, 4H), 3.72 - 3.61 (m, 4H), 3.25 (s, 3H), 2.84 - 2.83 (m, 2H), 2.78 - 2.76 (m, 2H), 2.02 - 1.86 (m, 2H) ppm 652 507.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.51 - 9.50 (m, 1H), 8.93 (s, 1H), 8.85 (s, 1H), 8.55 - 8.47 (m, 1H), 8.26 - 8.21 (m, 1H), 8.20 (s, 1H), 8.16 - 8.05 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.36 - 7.19 (m, 2H), 4.97 (s, 2H), 4.72 - 4.61 (m, 2H), 4.28 - 4.17 (m, 2H), 3.89 - 3.79 (m, 1H), 3.72 - 3.64 (m, 2H), 3.53 - 3.43 (m, 1H), 3.02 (dt, J = 6.2, 10.4 Hz, 1H), 2.87 - 2.71 (m, 1H), 2.03 - 1.88 (m, 1H), 1.84 - 1.53 (m, 6H), 1.47 - 1.13 (m, 3H) ppm 653 531.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.60 - 9.50 (m, 1H), 8.98 (s, 1H), 8.67 (br d, J =8.8 Hz, 1H), 8.52 (s, 1H), 8.40 (br s, 2H), 8.29 - 8.22 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.20 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.80 - 6.79 (m, 1H), 4.98 (s, 2H), 4.71 (brd, J = 6.0 Hz, 2H), 4.26 - 4.17 (m, 4H), 3.73 (s, 3H), 3.- 3.66 (m, 2H), 3.21 (brs, 2H) ppm 654 535.1 1H NMR (400 MHz, DMSO-d6) 0 = 9.57- 9.50 (m, 1H), 9.15-9.01 (m, 1H), 8.(d, J = 2.0 Hz, 1H), 8.54 (s, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.29 - 8.19 (m, 1H), 7.(d, J = 7.8 Hz, 1H), 7.59 - 7.50 (m, 1H), 7.34 - 7.22 (m, 2H), 7.00 -6.98 (m, 1H), 5.05 - 4.90 (m, 2H), 4.74 (d, J = 5.8 Hz, 2H), 4.33 -4.17 (m, 4H), 3.73 - 3.60 (m, 2H), 3.27 - 3.20 (m, 2H) ppm 655 602.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.60 (m, 1H), 9.40 (s, 1H), 8.72 - 8.57 (m, 3H), 8.51 - 8.41 (m, 1H), 8.33 - 8.25 (m, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.80 - 7.(m, 3H), 7.03 (d, J = 8.6 Hz, 1H), 4.82 (br d, J = 5.6 Hz, 2H), 4.31 (br d, J = 11.Hz, 2H), 4.02 - 3.90 (m, 2H), 3.85 - 3.75 (m, 2H), 3.72 - 3.62 (m, 2H), 2.41 - 2.(m, 2H), 1.64 (s, 6H), 1.21 (d, J = 6.2 Hz, 6H) ppm 656 516.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.56 (m, 1H), 9.17 - 9.02 (m, 2H), 8.(d, J = 1.8 Hz, 1H), 8.36 (d, J = 9.2 Hz, 1H), 8.25 - 8.24 (m, 1H), 8.21 (br s, 1H), 7.97 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.56 - 7.42 (m, 2H), 4.98 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.32 - 4.31 (m, 2H), 4.26 - 4.18 (m, 2H), 3.71 - 3.65 (m, 2H), 3.12 - 3.10 (m, 2H), 2.24 (s, 3H) ppm 281 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 657 528 1H NMR (400 MHz, METHANOL-d4) 6 = 9.36 (s, 1H), 8.86 (s, 1H), 8.74 (s, 1H), 8.68 - 8.62 (m, 2H), 8.28 - 8.20 (m, 2H), 8.03 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.(s, 1H), 5.06 (s, 2H), 4.97 (s, 2H), 4.39 - 4.31 (m, 2H), 3.94 (s, 3H), 3.60 - 3.51 (m, 2H), 2.61 (s, 3H) ppm 658 546.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.58 (m, 1H), 9.09 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.42 - 8.39 (m, 1H), 8.38 (br s, 1H), 8.32 - 8.23 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.8 Hz, 2H), 4.32 (s, 4H), 4.26 - 4.19 (m, 2H), 3.73 - 3.65 (m, 2H), 2.67 - 2.62 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H) ppm 659 586.4 1H NMR (400 MHz, DMSO-d6) 5 = 9.58 - 9.57 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.44-8.33 (m, 1H), 8.25 - 8.23 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.(d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H),7.48 (s, 1H), 7.04 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H), 4.79 - 4.70 (m, 3H), 4.26 - 4.(m, 2H), 4.18-4.06 (m, 2H), 3.98-3.91 (m, 1H), 3.85- 3.77 (m, 1H), 3.72-3.(m, 2H), 2.80 - 2.78 (m, 2H), 2.23 - 2.17 (m, 1H), 2.00 - 1.93 (m, 2H), 1.91 - 1.(m, 3H) ppm 660 594.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.58- 9.57 (m, 1H), 9.12 (s, 1H), 8.53 (d, J =1.6 Hz, 1H), 8.30 - 8.23 (m, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 4.98 (s, 2H), 4.75 (brd, J = 5.6 Hz, 2H), 4.41 (s, 2H), 4.25 - 4.20 (m, 2H), 4.17 - 4.11 (m, 2H), 3.71 - 3.66 (m, 2H), 3.35 (s, 3H), 2.84 - 2.82 (m, 2H), 2.01 -1.91 (m, 2H) ppm 661 544.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.62 - 9.61 (m, 1H), 9.36 (s, 1H), 8.62 (s, 2H), 8.54 (d, J = 1.8 Hz, 1H), 8.37 (br s, 1H), 8.26 - 8.24 (m, 1H), 7.81 - 7.69 (m, 3H), 7.34 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.27 - 4.20 (m, 2H), 3.71 - 3.65 (m, 2H), 3.42 - 3.39 (m, 1H), 3.20 (s, 3H), 3.09 -3.07 (m, 1H), 2.83 - 2.81 (m, 1H), 2.44 (brd, J = 9.8 Hz, 1H), 2.15-2.02 (m, 1H), 1.03 (d, J=6.8 Hz, 3H) ppm 662 544.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62-9.61 (m, 1H), 9.36 (s, 1H), 8.62 (s, 2H), 8.54 (d, J = 1.8 Hz, 1H), 8.37 (brs, 1H), 8.26 - 8.24 (m, 1H), 7.81 - 7.69 (m, 3H), 7.34 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.27 - 4.20 (m, 2H), 3.71 - 3.65 (m, 2H), 3.42 - 3.39 (m, 1H), 3.20 (s, 3H), 3.09 -3.07 (m, 1H), 2.83 - 2.81 (m, 1H), 2.44 (brd, J = 9.8 Hz, 1H), 2.15 - 2.02 (m, 1H), 103 (d, J = 6.8 Hz. 3H) ppm 282 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 663 600.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 -9.58 (m, 1H), 9.06 (s, 1H), 8.53 (d, J = 1.Hz, 1H), 8.45 - 8.39 (m, 1H), 8.25 - 8.24 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H),7.48 (s, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.73 (br d, J = 5.6 Hz, 2H), 4.- 4.16 (m, 3H), 4.13 - 4.04 (m, 1H), 3.73 - 3.63 (m, 2H), 3.46 (br d, J = 8.2 Hz, 1H), 3.19 (s, 3H), 2.82 - 2.80 (m, 2H), 1.96 - 1.94 (m, 2H), 1.16 - 1.00(m, 1H), 0.63 - 0.22 (m, 4H) ppm 664 600.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.59 - 9.58 (m, 1H), 9.07 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.46 (s, 1H), 8.26 -8.24 (m, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.74 (brd, J = 5.6 Hz, 2H), 4.27 -4.(m, 3H), 4.13 - 4.05 (m, 1H), 3.71 - 3.66 (m, 2H), 3.46 (s, 1H), 3.20 (s, 3H), 2.82 - 2.80 (m, 2H), 1.97- 1.95 (m, 2H), 1.16-1.10 (m, 1H), 0.59- 0.25 (m, 4H) ppm 665 546.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.60 - 9.51 (m, 1H), 9.08 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.47 - 8.43 (m, 1H), 8.34 - 8.22 (m, 3H), 7.80 (d, J = 2.0 Hz, 1H), 7.(d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.23 (d, J = 2.0 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.33 (s, 4H), 4.26 - 4.20 (m, 2H), 3.71 - 3.64 (m, 2H), 2.60 - 2.54 (m, 2H), 1.20-1.16 (m, 3H) ppm 666 571.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.56 - 9.53 (m, 1H), 8.96 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 2.8 Hz, 1H), 7.40 (s, 1H), 6.78 (d, J = 2.8 Hz, 1H), 4.98 (s, 2H), 4.70 (d, J = 6.0 Hz, 2H), 4.27 - 4.20 (m, 2H), 4.12 - 4.05 (m, 2H), 3.86 - 3.84 (m, 4H), 3.72 - 3.64 (m, 2H), 2.76 - 2.73 (m, 2H), 2.38 - 2.33 (m, 2H), 1.96 - 1.82 (m, 2H) ppm 667 613.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.39 (s, 1H), 9.32 - 9.31 (m, 1H), 8.69 - 8.61 (m, 2H), 8.35 (d, J = 2.0 Hz, 1H), 8.09 - 8.07 (m, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.39 (d, J = 9.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.78 (brd, J = 5.Hz, 2H), 4.32 (brd,J=11 .2 Hz, 2H), 3.97 - 3.94 (m, 1H), 3.76 - 3.64 (m, 3H), 3.- 3.52 (m, 1H), 2.78 - 2.71 (m, 1H), 2.52 (m, 2H), 1.25 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.0 Hz, 6H), 0.99 - 0.97 (m, 2H), 0.74 - 0.73 (m, 2H) ppm 668 574.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.62 (m, 1H), 9.39 (s, 1H), 8.66 (s, 2H), 8.53 (d, Je:1.8 Hz, 1H), 8.28 - 8.27 (m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.76 - 7.69 (m, 2H), 7.08 (d, J = 8.2 Hz, 1H), 4.97 (s, 2H), 4.82 (br d, J= 4.4 Hz, 2H), 4.32 - 4.27 (m, 1H), 4.05 - 3.99 (m, 1H), 3.69 - 3.63 (m, 1H), 3.54 - 3.49 (m, 1H), 3.26 (s, 3H), 3.24 (s, 3H), 2.65 - 2.63 (m, 1H), 1.17 (d, J = 7.0 Hz, 3H), 1.14-1.09 (m, 1H), 0.78 - 0.77 (m, 1H) ppm 283 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 669 574.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.62 (m, 1H), 9.39 (s, 1H), 8.66 (s, 2H), 8.53 (d, J = 1.6 Hz, 1H), 8.28-8.27 (m, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.78 - 7.67 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 4.97 (s, 2H), 4.82 (br d, J= 5.6 Hz, 2H), 4.29 - 4.27 (m, 1H), 4.02 - 4.00 (m, 1H), 3.70 - 3.61 (m, 1H), 3.54 - 3.50 (m, 1H), 3.26 (s, 3H), 3.24 (s, 3H), 2.68-2.62 (m, 1H), 1.17 (d, J = 7.0 Hz, 3H), 1.14- 1.08 (m, 1H), 0.82 - 0.74 (m, 1H) ppm 67Q 574.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.61 (m, 1H), 9.38 (s, 1H), 8.65 (s, 2H), 8.52 (d, J = 1.8 Hz, 1H), 8.41 - 8.33 (m, 1H), 8.27 - 8.26 (m, 1H), 7.91 (d, J = 7.Hz, 1H), 7.82 (s, 1H), 7.79 - 7.71 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 4.96 (s, 2H), 4.81 (br d, J = 5.6 Hz, 2H), 4.28 - 4.27 (m, 1H), 4.01 - 3.99 (m, 1H), 3.69 - 3.61 (m, 1H), 3.41 -3.40 (m, 1H), 3.37 (s, 3H), 3.19 (s, 3H), 2.73-2.67 (m, 1H), 1.20-1.(m, 1H), 1.16 (d, J = 7.2 Hz, 3H), 0.96 - 0.84 (m, 1H) ppm 671 571.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.36 (s, 1H), 8.64 - 8.59 (m, 2H), 8.21 - 8.18 (m, 1H), 7.88 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.34 - 7.28 (m, 1H), 5.04 (s, 2H), 4.93 (s, 2H), 4.63 - 4.58 (m, 2H), 4.56 - 4.48 (m, 2H), 4.36 - 4.31 (m, 2H), 3.68 - 3.64 (m, 1H), 3.63 (s, 2H), 3.54 - 3.51 (m, 2H), 3.08 - 3.05 (m, 2H), 2.71 - 2.68 (m, 2H) ppm 672 574.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.64 - 9.63 (m, 1H), 9.40 (s, 1H), 8.66 (s, 2H), 8.53 (d, J = 1.6 Hz, 1H), 8.29 - 8.27(m, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.84 (s, 1H), 7.80 - 7.73 (m, 2H), 7.09 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.82 (br d, J = 5.6 Hz, 2H), 4.30-1 - 4.28 (m, 1H), 4.05 - 4.00 (m, 1H), 3.70 - 3.62 (m, 1H), 3.42 - 3.41 (m, 1H), 3.38 (s, 3H), 3.20 (s, 3H), 2.72 - 2.71 (m, 1H), 1.24 - 1.19 (m, 1H), 1.17 (d, J = 7.2 Hz, 3H), 0.94 - 0.88 (m, 1H) ppm 673 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.61 (m, 1H), 9.39 (s, 1H), 9.20 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.27 - 8.24 (m, 1H), 8.06 - 7.95 (m, 2H), 7.83 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.42 - 7.46 (m, 1H), 4.98 (s, 2H), 4.84 (d, J = 5.6 Hz, 2H), 4.69 - 4.66 (m, 2H), 4.- 4.21 (m, 2H), 3.88 - 3.85 (m, 2H), 3.69 - 3.64 (m, 2H), 3.18 (s, 3H) ppm 674 573.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.62-9.61 (m, 1H), 9.41 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.39 (s, 2H), 8.23 - 8.22 (m, 1H), 7.81 - 7.(m, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.26 - 7.21 (m,1H), 4.96 (s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.26 - 4.18 (m, 2H), 3.70 - 3.63 (m, 4H), 3.32 - 3.32 (m, 2H), 3.06 (s, 3H), 2.95 - 2.87 (m, 2H), 2.77 - 2.69 (m, 2H), 2.54 - 2.52 (m, 2H) ppm 675 579 1H NMR (400 MHz, METHANOL-d4) 5 = 9.39 (s, 1H), 8.67 - 8.59 (m, 2H), 8.22 - 8.21 (m, 1H), 7.93 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.40 - 7.28 (m, 3H), 6.09 - 5.74 (m, 1H), 5.06 (s, 2H), 4.96 (br s, 2H), 4.39 - 4.32 (m, 2H), 3.86 (s, 2H), 3.57 - 3.51 (m, 2H), 3.08 - 3.03 (m, 2H), 2.99 - 2.95 (m, 2H), 2.85 - 2.84 (m, 2H) ppm 284 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 676 601.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.56 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.25- 5.24 (m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.39 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.92 (d, J= 2.4 Hz, 1H), 6.71 - 6.70 (m, 1H), 4.97 (s, 2H), 4.77 - 4.63 (m, 4H), 4.38 - 4.82 (m, 2H), 4.27 - 4.19 (m, 2H), 4.13 (d, J = 6.8 Hz, 2H), 3.97 - 3.96 (m, 2H), 3.73 - 3.(m, 2H), 3.46 (br s, 1H), 2.68 - 2.63 (m, 2H), 2.52 (br s, 1H), 1.89 - 1,87 (m, 2H) ppm 677 572.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.58 - 9.55 (m, 1H), 9.05 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.26-8.24 (m, 1H), 8.19 - 8.13 (m, 1H),8.09(d,J=5.6 Hz, 1H), 7.(d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.06 (d, J = 5.6 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.23 - 4.22 (m, 2H), 4.16 - 4.09 (m, 2H), 4.- 3.99 (m, 1H), 3.73 - 3.66 (m, 2H), 2.62 - 2.59 (m, 2H), 1.94 - 1.85 (m, 2H), 0.89 - 0.81 (m, 2H), 0.76 - 0.68 (m, 2H) ppm 678 537.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.66 - 9.65(m, 1H), 9.45 (s, 1H), 8.74 (d, J = 8.Hz, 2H), 8.69 - 8.64 (m, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.27 - 8.25 (m, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.86 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H), 4.84 (d, J = 5.Hz, 2H), 4.27 - 4.19 (m, 2H), 3.72 - 3.64 (m, 2H), 3.17 - 3.10 (m, 2H), 2.81 - 2.(m, 2H) ppm 679 531.3 1H NMR (400 MHz, DMSO-d6) 0 9.18 (s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.(dd, J = 7.7, 1.9 Hz, 1H), 8.05-7.95 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.79 (s, 5H), 5.01 (s, 2H), 4.(d, J = 5.8 Hz, 2H), 4.35 (t, J = 4.4 Hz, 2H), 4.30 - 4.23 (m, 2H), 4.05 - 3.98 (m, 2H), 3.73 — 3.66 (m, 2H), 2.25 (s, 3H). 68Q 545.3 1H NMR (400 MHz, DMSO-d6) 0 9.56 (t, J = 5.9 Hz, 1H), 9.18 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.30 (dd, J = 7.8, 1.9 Hz, 1H), 8.05 - 7.94 (m, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.99 (s, 2H), 4.76 (d, J = 5.7 Hz, 2H), 4.38-4.29 (m, 3H), 4.10-3.98 (m, 3H), 3.- 3.63 (m, 1H), 2.25 (s, 3H), 1.20 (d, J = 7.0 Hz, 3H). 681 545.3 1H NMR (400 MHz, METHANOL-d4) 5 = 9.01 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.(d, J = 1.6 Hz, 1H), 8.21 -8.19 (m, 1H), 8.16 (d, J: 8.8 Hz, 1H), 7.96 (d, J = 9.Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.66 - 7.63 (m, 2H), 6.95 (d, J = 4.8 Hz, 1H), 5.(s, 2H), 4.85 (s, 2H), 4.36 - 4.33 (m, 2H), 4.31 - 4.25 (m, 2H), 3.54 - 3.51 (m, 2H), 3.30 - 3.27 (m, 2H), 2.83 (s, 3H), 2.39 (s, 3H) ppm 682 581.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.56 (m, 1H), 9.07 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.26 - 8.22 (m, 1H), 7.76 - 7.69 (m, 2H), 7.(d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.23 - 7.21 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 4.(s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.36 - 4.30 (m, 2H), 4.24 - 4.20 (m, 4H), 3.70 - 3.65 (m, 2H), 1.95 - 1.86 (m, 3H) ppm 285 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 683 586.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.56 (m, 1H), 9.Q5 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.25 - 8.23 (m, 7.9 Hz, 1H), 8.15 (d, J = 9.6 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.48 (s, 1H), 7.28 (s, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.2 Hz, 2H), 4.27 - 4.17 (m, 2H), 4.13 - 4.07 (m, 2H), 3.84 (s, 3H), 3.72 - 3.64 (m, 2H), 2.80 - 2.77 (m, 2H), 2.- 2.33 (m, 1H), 1.94 - 1.88 (m, 2H), 0.90 - 0.74 (m, 4H) ppm 684 574.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.56 - 9.46 (m, 1H), 9.39 (s, 1H), 8.70 - 8.58 (m, 2H), 8.49 - 8.43 (m, 1H), 8.17 - 8.15 (m, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.81 - 7.(m, 2H), 7.28 - 7.20 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.89 - 4.75 (m, 3H), 4.67 - 4.57 (m, 1H), 4.32 (br d, J = 11.4 Hz, 2H), 4.03 - 3.90 (m, 1H), 3.74 - 3.61 (m, 2H), 2.52 (br s, 2H), 1.34 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H) ppm 685 555.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.64 - 9.61 (m, 1H), 9.43 (s, 1H), 8.66 - 8.64 (m, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.24 - 8.22 (m, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.26 - 7.22 (m, 1H), 4.(s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.26 - 4.17 (m, 2H), 3.74 (s, 2H), 3.70 - 3.61 (m, 2H), 2.94 - 2.84 (m, 4H), 1.72 - 1.69 (m, 1H), 0.38 - 0.30 (m, 2H), 0.28 -0.17 (m, 2H) ppm 686 557.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.61 - 9.50 (m, 1H), 9.04 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.72 (d, J = 6.0 Hz, 2H), 4.23 (d, J = 4.8 Hz, 4H), 3.- 3.64 (m, 2H), 3.42 - 3.39 (m, 2H), 2.46 - 2.43 (m, 1H), 0.91 - 0.81 (m, 2H), 0.66 - 0.56 (m, 2H) ppm 687 574 1H NMR (400 MHz, DMSO-d6) 0 = 9.56 - 9.45 (m, 1H), 9.39 (s, 1H), 8.65 - 8.61 (m, 2H), 8.48 (d, J = 0.8 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.(d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 4.86 - 4.75 (m, 3H), 4.62 (d, J = 8.4 Hz, 1H), 4.31 (d, J = 11.6 Hz, 2H), 4.04 - 3.92 (m, 1H), 3.72 - 3.63 (m, 2H), 2.56 - 2.54 (m, 2H), 1.34 (d, J = 7.2 Hz, 3H), 1.21 (d, J = 6.0 Hz, 6H) ppm 688 519.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.55 - 9.49 (m, 1H), 8.90 (s, 1H), 8.60 (d, J = 9.2 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.24-8.23 (m, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.31 (s, 1H), 4.97 (s, 2H), 4.67 (d, J = 5.4 Hz, 2H), 4.26 - 4.13 (m, 4H), 3.67 - 3.65 (m, 2H), 3.57 (s, 3H), 2.66 - 2.64 (m, 2H), 2.- 1.92 (m, 2H) ppm 689 592.1 1H NMR (400 MHz, METHANOL-d4) 6 = 9.00 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.- 8.20 (m, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.52 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 5.04 (s, 2H), 4.85 (s, 2H), 4.37 - 4.30 (m, 3H), 4.09 - 4.07 (m, 1H), 3.52 - 3.51 (m, 2H), 2.95 - 2.84 (m, 3H), 2.11 -2.00 (m, 3H), 1.79- 1.67 (m, 1H) ppm 286 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 690 592.1 1H NMR (400 MHz, METHANOL-d4) 6 = 9.00 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.- 8.19 (m, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.68 - 7.61 (m, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 5.04 (s, 2H), 4.84 (s, 2H), 4.39 - 4.29 (m, 3H), 4.09 - 4.07 (m, 1H), 3.55 - 3.49 (m, 2H), 2.96 - 2.82 (m, 3H), 2.11 -2.02 (m, 3H), 1.77- 1.67 (m, 1H) ppm 691 569.8 1H NMR (400 MHz, DMSO-d6) 5 = 9.65 - 9.64 (m, 1H), 9.13 (s, 1H), 8.40 (d, J = 1.4 Hz, 1H), 8.33 (d, J = 9.4 Hz, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.16-8.15 (m, 1H), 7.98 - 7.93 (m, 1H), 7.56 - 7.52 (m, 2H), 5.02 (s, 2H), 4.74 (br d,J= 5.4 Hz, 2H), 4.41 - 4.32 (m, 4H), 4.27 - 4.19 (m, 2H), 3.81 - 3.72 (m, 2H) ppm 692 586.9 1H NMR (400 MHz, DMSO-d6) 5 = 9.61 - 9.49 (m, 1H), 9.00 (s, 1H), 8.52 (d, J =1.6 Hz, 1H), 8.24 (dd, J = 2.0, 7.9 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.46 - 7.37 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.53 - 6.52 (m, 1H), 5.20 - 5.19 (m, 1H), 5.01 - 4.94 (m, 2H), 4.83 - 4.82 (m, 2H), 4.70 (br d, J = 5.6 Hz, 2H), 4.53 - 4.52 (m, 2H), 4.28 - 4.18 (m, 2H), 3.97 - 3.96 (m, 2H), 3.72 - 3.64 (m, 2H), 2.66 - 2.64 (m, 2H), 1.93 - 1.85 (m, 2H) ppm 693 417.91H NMR (400 MHz, DMSO-d6) 0 = 9.63 - 9.61 (m, 1H), 9.42 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.49 (s, 1H), 8.24 - 8.21 (m, 1H), 7.74 - 7.71 (m, 3H), 4.98 (s, 2H), 4.(br d, J = 5.6 Hz, 2H), 4.23 - 4.21 (m, 2H), 3.68 - 3.65 (m, 2H) ppm 694 544.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62-9.61 (m, 1H), 9.36 (s, 1H), 8.62 (s, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.33 (br s, 1H), 8.26 - 8.24 (m, 1H), 7.83 - 7.69 (m, 3H), 7.43 (d, J = 8.2 Hz, 1H), 4.98 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.30-4.18 (m, 2H), 3.72 - 3.65 (m, 2H), 3.43 (brs, 2H), 3.21 (s, 3H), 2.99 - 2.88 (m, 1H), 1.97 - 1.95 (m, 1H), 1.72 - 1.59 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H) ppm 695 544.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62-9.61 (m, 1H), 9.36 (s, 1H), 8.62 (s, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.33 (brs, 1H), 8.26 - 8.24 (m, 1H), 7.83 - 7.69 (m, 3H), 7.43 (d, J = 8.2 Hz, 1H), 4.98 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.30 - 4.18 (m, 2H), 3.72 - 3.65 (m, 2H), 3.43 (brs, 2H), 3.21 (s, 3H), 2.99 - 2.88 (m, 1H), 1.97 - 1.95 (m, 1H), 1.72 - 1.59 (m, 1H), 1.25 (d, J = 6.8 Hz, 3H) ppm 696 603.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59-9.51 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.53- 8.52 (m, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.47 - 7.33 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 4.98 (s, 2H), 4.70 (d, J = 6.0 Hz, 2H), 4.51 - 4.42 (m, 1H), 4.26 - 4.19 (m, 2H), 3.97 - 3.95(m, 2H), 3.70 - 3.65 (m, 2H), 3.43 (d, J = 6.0 Hz, 2H), 3.25 (s, 3H), 2.67-2.63 (m, 2H), 1.94-1.85 (m, 2H), 1.16 (d, J = 6.Hz, 3H) ppm 287 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 697 603.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.50 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.43-8.34 (m, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.37 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 4.97 (s, 2H), 4.70 (d, J = 5.Hz, 2H), 4.47 (d, J = 6.0 Hz, 1H), 4.26 - 4.19 (m, 2H), 3.97 (d, J = 6.4 Hz, 2H), 3.- 3.64 (m, 2H), 3.42 (d, J = 6.0 Hz, 1H), 3.39 (d, J = 4.0 Hz, 1H), 3.25 (s, 3H), 2.66 - 2.63 (m, 2H), 1.92 - 1.87 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H) ppm 698 592.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.67 - 9.51 (m, 1H), 9.13 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.32 (s, 1H), 8.25 - 8.23 (m, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 4.97 (s, 2H), 4.(d, J = 6.0 Hz, 2H), 4.35 - 4.20 (m, 6H), 3.71 - 3.65 (m, 2H), 2.37 - 2.34 (m, 1H), 0.97 - 0.91 (m, 2H), 0.87 - 0.81 (m, 2H) ppm 699 570.1 1H NMR (400 MHz, METHANOL-d4) 6 = 9.35 (s, 1H), 8.75 - 8.70 (m, 1H), 8.68 - 8.60 (m, 2H), 8.57 - 8.51 (m, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.24 - 8.23 (m, 1H), 8.(s, 1H), 7.94 - 7.93 (m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 5.(s, 2H), 4.95 (s, 2H), 4.43 - 4.33 (m, 2H), 3.59 - 3.52 (m, 3H), 3.07 - 2.92 (m, 3H), 2.79-2.70 (m, 1H), 2.61 (s, 3H), 2.45 - 2.43 (m, 1H), 2.27 - 2.11 (m, 1H), 1.57- 1.55 (m, 1H), 1.21 - 1.19 (m, 1H) ppm 700 594.1 1H NMR (400 MHz, METHANOL-d4) 0 = 9.03 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.- 8.24 (m, 1H), 8.23 - 8.17 (m, 2H), 7.69 - 7.57 (m, 2H), 7.25 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 5.04 (s, 2H), 4.85 (br s, 2H), 4.65 - 4.60 (m, 1H), 4.39 - 4.37 (m, 1H), 4.36 - 4.27 (m, 3H), 4.19 - 4.10 (m, 1H), 3.52 - 3.50 (m, 2H), 2.97 - 2.85 (m, 1H), 2.10-2.01 (m, 1H), 1.84- 1.72 (m, 1H) ppm 701 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65- 9.63 (m, 1H), 9.37 (s, 1H), 9.18 (d, J = 8.8 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.59 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.45 - 8.40 (m, 1H), 8.28 - 8.26 (m, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.29 - 7.22 (m, 1H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.72 - 4.(m, 2H), 4.27 - 4.19 (m, 2H), 3.91 - 3.89 (m, 2H), 3.71 - 3.66 (m, 2H), 3.26 (s, 3H) ppm 702 594.1 1H NMR (400 MHz, METHANOL-d4) 5 = 9.02 (s, 1H), 8.61 (d, J 1.6 Hz, 1H), 8.- 8.24 (m, 1H), 8.24 - 8.17 (m, 2H), 7.69 - 7.60 (m, 2H), 7.26 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 5.05 (s, 2H), 4.94 (br d, J = 1.8 Hz, 2H), 4.65 - 4.60 (m, 1H), 4.44 - 4.38 (m, 1H), 4.36 - 4.28 (m, 3H), 4.22 - 4.20 (m, 1H), 3.55 - 3.51 (m, 2H), 2.91 -2.90 (m, 1H), 2.17-1.96 (m, 1H), 1.89- 1.67 (m, 1H) ppm 703 532.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.52 (m, 1H), 9.11 - 9.02 (m, 2H), 8.57 - 8.50 (m, 1H), 8.48 - 8.44 (m, 1H), 8.39 - 8.31 (m, 1H), 8.29 - 8.22 (m, 1H), 7.85 (d, J = 2.4 Hz, 1H). 7.77 - 7.71 (m, 1H), 7.48 - 7.44 (m, 1H), 7.41 (brs, 1H), 4.98 (s, 2H), 4.72 (br d, J = 5.8 Hz, 2H), 4.37 - 4.30 (m, 2H), 4.26 - 4.19 (m, 2H), 3.80 (s, 3H), 3.70 - 3.66 (m, 2H), 3.17 - 3.13 (m, 2H) ppm 288 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 704 600.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.60 - 9.53 (m, 1H), 9.39 (s, 1H), 8.69 - 8.59 (m, 2H), 8.50 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.24 - 8.22 (m, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.80 (s, 1H), 7.77 - 7.71 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.80 (d, J = 5.6 Hz, 2H), 4.31 (d, 3 =11.6 Hz, 2H), 3.70 - 3.65 (m, 2H), 3.64 - 3.61 (m, 2H), 2.53 (s, 2H), 2.32 (d, J = 2.0 Hz, 2H), 1.21 (d, J = 6.0 Hz, 6H), 0.98 - 0.92 (m, 2H), 0.76 - 0.70 (m, 2H) ppm 705 603.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.56 - 9.54 (m, 1H), 8.98 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.43 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.38 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.(d, J = 2.4 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 4.69 (d, J = 6.0 Hz, 2H), 4.27 - 4.18 (m, 2H), 4.00 - 3.93 (m, 2H), 3.87 - 3.82 (m, 2H), 3.69 - 3.64 (m, 2H), 3.61 (d,J = 6.Q Hz, 1H), 3.26 (s, 3H), 2.67 - 2,63 (m, 2H), 1.92- 1.85 (m, 2H), 1.(d, J = 6.4 Hz, 3H) ppm 706 603.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.54 - 9.53 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.37- 8.28 (m, 1H), 8.24 - 8.23 (m, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.73(d, J = 7.8 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.39 (s, 1H), 7.13 (d, J =8.4 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.69 - 6.68 (m, 1H), 4.98 (s, 2H), 4.70 (d, J =5.8 Hz, 2H), 4.25 - 4.20 (m, 2H), 3.97 - 3.95 (m, 2H), 3.87 - 3.84 (m, 2H), 3.71 -3.65 (m, 2H), 3.60 (s, 1H), 3.27 (s, 3H), 2.71 - 2.65 (m, 2H), 1.89 - 1.87 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H) ppm 707 574.3 1H NMR (400 MHz, DMSO-d6) 6 8.52 (s, 1H), 8.05 (s, 1H), 7.86 - 7.75 (m, 2H), 7.56 (d, J = 6.2 Hz, 1H), 7.47-7.36 (m, 2H), 7.16 (s, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.01 (d, J = 6.3 Hz, 1H), 4.27 (s, 2H), 4.13 (s, 2H), 3.60 - 3.52 (m, 2H), 2.98 - 2.(m, 1H), 2.75 (d, J = 5.3 Hz, 2H), 2.08 - 1.88 (m, 3H), 0.65 - 0.41 (m, 6H). 708 588.4 1H NMR (400 MHz, Methanol-d4) 6 9.28 (s, 1H), 8.81 (d, J = 1.3 Hz, 1H), 8.(d, J = 1.9 Hz, 1H), 8.55 (dd, J = 8.6, 1.6 Hz, 1H), 8.32 (d, J = 6.3 Hz, 1H), 8.(dd, J = 7.8, 1.9 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 6.3 Hz, 1H), 5.08-4.95 (m, 2H), 4.89 (s, 2H), 4.49 (s, 2H), 4.42 - 4.34 (m, 1H), 4.09 (dd, J = 13.3, 5.8 Hz, 1H), 3.70 (ddd, J = 10.5, 6.2, 2.7 Hz, 1H), 2.73 - 2.60 (m, 3H), 1.28 - 1.20 (m, 9H). 709 586.3 1H NMR (400 MHz, Methanol-d4) 6 9.29 (s, 1H), 8.69 (d, J = 8.7 Hz, 1H), 8.64 - 8.53 (m, 1H), 8.42 (s, 3H), 8.22 (dd, J = 7.8, 1.9 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.72 - 7.60 (m, 2H), 6.67 (d, J = 8.3 Hz, 1H), 5.12 (s, 1H), 5.09 - 4.(m, 2H), 4.92 (s, 2H), 4.38 (dd, J = 13.3, 2.4 Hz, 1H), 4.09 (dd, J = 13.3, 5.9 Hz, 1H), 4.00 (dd, J = 8.8, 6.7 Hz, 1H), 3.80-3.66 (m, 3H), 3.59-3.52 (m, 3H), 3.(d, J = 4.0 Hz, 1H), 2.15 (s, 3H), 1.60 (s, 1H), 1.37 (dd, J = 7.0, 2.0 Hz, 2H). 289 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 710 589.4 1H NMR (400 MHz, DMSO-d6) 6 10.00 (s, 1H), 9.69 (t, J = 5.8 Hz, 1H), 9.54 (s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.31 (dd, J = 7.9, 1.9 Hz, 1H), 7.97 (s, 1H), 7.(d, J = 7.3 Hz, 1H), 7.87-7.75 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 5.01 (s, 2H), 4.(d, J = 5.8 Hz, 2H), 4.36 (dd, J = 20.9, 11.8 Hz, 2H), 4.06 (dd, J = 13.4, 5.9 Hz, 1H), 3.74 - 3.66 (m, 5H), 3.03 (s, 1H), 3.01 (s, 7H), 1.26 (d, J = 6.2 Hz, 6H), 1.21 (d, J = 7.1 Hz, 3H). 711 577.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.49 (m, 1H), 9.01 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.47 (s , 1H), 8.29 -8.16 (m, 2H), 7.72 (d,Js 8.0 Hz, 1H), 7.41 - 7.(m, 1H), 7.25 - 7.15 (m, 1H), 7.13 - 7.06 (m, 1H), 6.98 (d, J = 9.2 Hz, 1H), 4.97(s, 2H), 4.70 (d, J = 5.2 Hz, 2H), 4.43 (s, 2H), 4.28 - 4.17 (m, 2H), 4.15 - 3.89 (m, 2H), 3.71 - 3.63 (m, 2H), 3.27 - 3.24 (m, 3H), 2.78 - 2.75 (m, 2H), 1.97 - 1.84 (m, 2H) ppm 712 572.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.57 (m, 1H), 9.12-9.06 (m, 1H), 8.(d, J = 1.6 Hz, 1H), 8.32 - 8.23 (m, 3H), 7.84 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 7.Hz, 1H), 7.52 - 7.43 (m, 1H). 7.15 (d. J = 2.0 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.Hz, 2H), 4.34 - 4.30 (m, 4H), 4.25 - 4.20 (m, 2H), 3.70 - 3.66 (m, 2H), 1.39 (s, 3H), 0.93 - 0.82 (m, 2H), 0.80 - 0.70 (m, 2H) ppm 713 572.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60- 9.57 (m, 1H), 9.11 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.33 - 8.29 (m, 1H), 8.28 - 8.21 (m, 2H), 7.74 (d, J = 8.Hz, 1H), 7.50 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.34 - 4.26 (m, 4H), 4.26 - 4.21 (m, 2H), 3.71 - 3.(m, 2H), 1.44 (s, 3H), 1.07 - 1.01 (m, 2H), 0.76 - 0.70 (m, 2H) ppm 714 5563.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.55 - 9.54 (m, 1H), 9.00 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.24-8.23 (m, 1H),8.16(d,J=9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.16 (d, J = 7.8 Hz, 1H),7.11 (d, J = 11.6 Hz, 1H), 4.98 (s, 2H), 4.70 (brd, J = 5.6 Hz, 2H), 4.27-4.18 (m, 2H), 3.99 - 3.97 (m, 2H), 3.74 (s, 3H), 3.69 - 3.66 (m, 2H), 2.68 - 2.63 (m, 2H), 1.- 1.87 (m, 2H) ppm 715 592.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.62 (m, 1H), 9.40 (s, 1H), 8.72 - 8.60 (m, 2H), 8.52 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 8.28 - 8.27 (m, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.78 - 7.70 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 4.82 (brd, J = 5.Hz, 2H), 4.31 (br d, J = 12.0 Hz, 2H), 3.73 - 3.60 (m, 3H), 2.54 - 2.51 (m, 2H), 1.(d, J = 6.2 Hz, 6H), 1.16 (d, J = 7.0 Hz, 3H) ppm 716 561.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.55 - 9.54 (m, 1H), 9.04 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.29 (s, 1H), 8.28 - 8.22 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.46 - 7.44 (m, 1H), 7.42 (s, 1H), 7.11 - 7.03 (m, 1H), 7.01 - 6.96 (m, 1H), 6.95 - 6.88 (m, 1H), 4.97 (s, 2H), 4.71 (d, J = 6.0 Hz, 2H), 4.63 - 4.62 (m, 1H), 4.45 - 4.37 (m, 1H), 4.27 - 4.19 (m, 2H), 3.73 (dd, J = 7.7, 13.6 Hz, 1H), 3.70 - 3.(m, 2H), 3.59 - 3.48 (m, 2H), 3.21 (s, 3H) ppm 290 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 717 592.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.62 (m, 1H), 9.40 (s, 1H), 8.73 - 8.58 (m, 2H), 8.52 (d, J = 1.6 Hz, 1H), 8.42 (s, 1H), 8.28- 8.27 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.79 - 7.65 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 4.82 (br d, J = 5.Hz, 2H), 4.31 (br d, J = 11.6 Hz, 2H), 3.74 - 3.57 (m, 3H), 2.56 - 2.52 (m, 2H), 1.(d, J = 6.2 Hz, 6H), 1.16 (d, J = 7.2 Hz, 3H) ppm 718 563.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.54 - 9.53 (m, 1H), 9.02 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.26 - 8.19 (m, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.10 - 7.(m, 1H), 7.01 - 7.00 (m, 1H), 6.81 - 6.80 (m, 1H), 4.97 (s, 2H), 4.70 (d, J = 5.8 Hz, 2H), 4.22 - 4.20 (m, 2H), 3.81 (s, 3H), 3.72 - 3.64 (m, 2H), 3.30 (s, 2H), 2.67 - 2.(m, 2H), 1.84- 1.82 (m, 2H) 719 546.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.54 - 9.53 (m, 1H), 8.98 (s, 1H), 8.56 - 8.48 (m, 1H), 8.46 (brs. 1H), 8.33 - 8.08 (m, 3H), 7.72 (d, J = 7.8 Hz, 1H), 7.49 - 7.30 (m, 2H), 6.81 - 6.66 (m, 1H), 4.97 (s, 2H), 4.69 (br d, J = 6.0 Hz, 2H), 4.30 -4.17 (m, 2H), 3.98 - 3.96 (m, 2H), 3.84 (s, 3H), 3.70 - 3.64 (m, 2H), 2.72 - 2.70 (m, 2H), 1.- 1.84 (m, 2H) ppm 720 552.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.62 - 9.55 (m, 1H), 9.15 - 9.09 (m, 2H), 8.(d, J = 1.6 Hz, 1H), 8.47 (s, 1H), 8.45 (d, J = 9.4 Hz, 1H), 8.34 (s, 1H), 8.25 - 8.(m, 1H), 7.82 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.22-6.91 (m, 1H), 4.98 (s, 2H), 4.75 (d, J = 5.8 Hz, 2H), 4.40 - 4.38 (m, 2H), 4.25 - 4.20 (m, 2H), 3.- 3.66 (m, 2H), 3.22 (br d,J= 8.2 Hz, 2H) ppm 721 565 1H NMR (400 MHz, DMSO-d6) 6 = 9.87 - 9.73 (m, 1H), 9.48 (d, J = 1.6 Hz, 1H), 9.07 (s, 1H), 8.89 (s, 1H), 8.18 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.78 - 7.41 (m, 3H), 6.97 (d, J = 7.6 Hz, 1H), 4.78 (d, J = 5.6 Hz, 2H), 4.17 - 4.04 (m, 2H), 3.48 (s, 3H), 2.78 - 2.74 (m, 2H), 2.03 - 1.88 (m, 3H), 0.90 - 0.80 (m, 2H), 0.79 - 0.72 (m, 2H) ppm 722 572.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.57(m, 1H), 9.11 (s, 1H), 8.53 (d, J = 1.Hz, 1H), 8.46 (d, J = 9.2 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.33 (s, 4H), 4.26 - 4.20 (m, 2H), 3.71 - 3.65 (m, 2H), 3.57-3.51 (m, 1H), 2.29-2.16 (m, 4H), 2.00-1.90 (m, 1H), 1.87- 1.77 (m, 1H) ppm 723 556.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.57 (m, 1H), 9.08 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 8.26 - 8.25 (m, 1H), 8.18 (d, J = 9.2 Hz, 1H), 8.12-8(m, 1H), 8.04- 8.03 (m, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.(s, 1H), 7.14 - 7.13 (m, 1H), 4.99 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.27 - 4.20 (m, 2H), 4.14 - 4.08 (m, 2H), 3.73 - 3.67 (m, 2H), 2.38 - 2.32 (m, 2H), 2.14 -1.98 (m, 6H) ppm 291 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 724 565.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.80 - 9.77 (m, 1H), 9.48 (d, J = 2.0 Hz, 1H), 9.04(8, 1H), 8.89 (8, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.78 - 7.47 (m, 2H), 7.27 (d, J = 2.4 Hz, 1H), 4.77 (d, J = 5.6 Hz, 2H), 4.18- 4.03 (m, 2H), 3.48 (s, 3H), 2.79 - 2.76 (m, 2H), 2.00 - 1.86 (m, 3H), 1.- 0.91 (m, 2H), 0.75 - 0.66 (m, 2H) ppm 725 556.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.51 (m, 1H), 8.99 (s, 1H), 8.53 - 8.46 (m, 2H), 8.43 (brs, 1H), 8.27 - 8.15 (m, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.15 (s, 1H), 4.97 (s, 2H), 4.69 (d, J = 5.6 Hz, 2H), 4.27 - 4.18 (m, 2H), 3.99 (t, J = 6.2 Hz, 2H), 3.71 - 3.65 (m, 2H), 2.73 (t, J = 6.3 Hz, 2H), 2.54 (s, 1H), 2.10 - 2.00 (m, 1H), 1.90 (quin, J = 6.2 Hz, 2H), 0.99 - 0.79 (m, 4H) ppm 726 619.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.55 - 9.54 (m, 1H), 8.99 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.24-8.22 (m, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.48 - 7.35 (m, 2H), 7.23 - 7.07 (m, 2H), 4.97 (s, 2H), 4.70 (br d, J = 5.6Hz, 2H), 4.66 - 4.64 (m, 2H), 4.38 (t, J = 6.0 Hz, 2H), 4.22 - 4.20 (m, 2H), 4.18 (d, J = 6.8 Hz, 2H), 3.98 - 3.96 (m, 2H), 3.73 - 3.65 (m, 3H), 2.66 - 2.64 (m, 2H), 2.00 - 1.80 (m, 2H) ppm 727 520.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.55 (m, 1H), 9.09 (s, 1H), 9.01 (d, J = 9.2 Hz, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.39 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.70- 7.64 (m, 1H), 7.48 (s, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.39 - 4.37(m, 2H), 4.27 - 4.18 (m, 2H), 3.73 - 3.64 (m, 2H), 3.20 - 3.16 (m, 2H) ppm 728 587.4 1H NMR (400 MHz, DMSO-d6) 6 9.51 (t, J = 5.8 Hz, 1H), 9.35 (s, 1H), 8.64 (d, J = 1.5 Hz, 1H), 8.45-8.35 (m, 2H), 8.25-8.16 (m, 2H), 7.88 (s, 1H), 7.73 (dd, J = 8.5, 7.5 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.09 (s, 2H), 4.80 (d, J = 5.8 Hz, 2H), 4.34 (d, J = 12.2 Hz, 2H), 4.28-4.21 (m, 2H), 3.75-3.(m, 1H), 3.68 (s, 3H), 1.24 (d, J = 6.2 Hz, 6H). 729 557.4 1H NMR (400 MHz, Methanol-d4) 6 9.08 (s, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.51 (s, 1H), 8.19 (dd, J = 7.8, 1.9 Hz, 1H), 7.99-7.89 (m, 2H), 7.67 (s, 1H), 7.66-7.(m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.04 (s, 2H), 4.84 (s, 2H), 4.37 - 4.29 (m, 4H), 4.03 - 3.97 (m, 2H), 3.52 (s, 1H), 3.55 - 3.48 (m, 1H), 1.88 - 1.80 (m, 1H), 0.73 (it, J = 7.6, 2.5 Hz, 4H). 730 570.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.57 (m, 1H), 9.07 (s, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.26 - 8.24 (m, 1H), 8.20 (d, J = 9.2 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.50 -7.48 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 4.99 (s, 2H), 4.74 (brd, J = 5.6 Hz, 2H), 4.27-4.20 (m, 2H), 4.19-4.08 (m, 2H), 3.71 - 3.66 (m, 2H), 3.53 (s, 1H), 2.79 - 2.78 (m, 2H), 2.26 - 2.16 (m, 4H), 2.- 1.91 (m, 3H), 1.83 - 1.75 (m, 1H) ppm 292 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 731 563.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.56-9.55 (m, 1H), 8.98 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.43 (s, 1H), 8.24- 8.23 (m, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.44 - 7.29 (m, 2H), 7.11 (d, J = 7.8 Hz, 2H), 4.97 (s, 2H),4.69 (d, J = 6.0 Hz, 2H), 4.26 - 4.19 (m, 2H), 4.00 - 3.98 (m, 2H), 3.87 (d, J = 1.Hz, 3H), 3.70 - 3.66 (m, 2H), 2.73 - 2.70 (m, 2H), 1.88 - 1.84 (m, 2H) ppm 732 560.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.54 (m, 1H), 9.03 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.36 (s, 1H), 8.29 - 8.21 (m, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 6.70 (s, 1H), 4.98 (s, 2H), 4.(d, J = 6.0 Hz, 2H), 4.28 - 4.19 (m, 2H), 4.16 - 4.07 (m, 2H), 3.86 (s, 3H), 3.72 - 3.65 (m, 2H), 2.65 - 2.59 (m, 2H), 2.34 (s, 3H), 1.98 - 1.83 (m, 2H) ppm 733 560.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.72-9.71 (m, 1H), 9.44-9.13 (m, 1H), 8.98 (s, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.33 - 8.25 (m, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.19 - 7.13 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.10 - 4.99 (m, 2H), 4.77 - 4.70 (m, 2H), 4.39 - 4.32 (m, 1H), 4.12-4.03 (m, 3H), 3.87-3.79 (m, 4H), 2.66 (d, J = 6.0 Hz, 2H), 1.97-1.(m, 2H), 1.23 - 1.19 (m, 3H) ppm 734 556.1 1H NMR (400 MHz, DMSO-d6) 0 = 9.61 - 9.48 (m, 1H), 9.04 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.32 (br s, 1H), 8.25 - 8.24 (m, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.95 - 7.85 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 7.07 (d, J = 2.2 Hz, 1H), 4.(s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.28 - 4.20 (m, 4H), 3.69 - 3.66 (m, 2H), 2.22 (s, 3H), 1.87- 1.79 (m, 2H), 1.10-1.03 (m, 2H), 0.96- 0.89 (m, 2H) ppm 735 601.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.55 - 9.52 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.25 - 8.23 (m, 1H), 8.15 (d, J = 9.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.73 - 6.70 (m, 1H), 5.03 - 4.91 (m, 3H), 4.70 (d, J = 5.6 Hz, 2H), 4.57 - 4.(m, 2H), 4.29 - 4.20 (m, 2H), 4.13 - 4.06 (m, 1H), 4.05 - 3.96 (m, 3H), 3.71 - 3.(m, 2H), 2.71 - 2.60 (m, 4H), 1.93 - 1.86 (m, 2H) ppm 736 549.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.56- 9.53 (m, 1H), 9.01 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.25 - 8.23 (m, 1H), 8.17 (d, J = 9.2 Hz, 1H). 7.73 (d, J = 7.6 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.33 - 7.27 (m, 1H), 7.26 - 7.19 (m, 1H), 6.80 (brd, J = 8.8 Hz, 1H), 4.98 (s, 2H), 4.71 (brd, J = 5.6 Hz, 2H), 4.26 - 4.21 (m, 2H), 3.70 - 3.65 (m, 3H), 3.52 - 3.45 (m, 2H), 2.73 (br d, J = 4.0 Hz, 2H), 1.97 - 1.80 (m, 2H) ppm 737 536.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.59- 9.58 (m, 1H), 9.10 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 9.2 Hz, 1H), 8.25 - 8.24 (m, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.45 - 7.43 (m, 1H), 4.97 (s, 2H), 4.73 (brd, J = 5.6 Hz, 2H), 4.36 - 4.34 (m, 4H), 4.28 - 4.18 (m, 2H), 3.71 - 3.65 (m, 2H) ppm 293 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 738 550.2 1H NMR (40Q MHz, DMSO-d6) 6 = 9.59- 9.58 (m, 1H), 9.10 (s, 1H), 8.51 (d, J =1.6 Hz, 1H), 8.30 (d, J = 9.2 Hz, 1H),8.26-8.24 (m, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 2.6 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.45 - 7.43 (m, 1H), 4.96 (s, 2H), 4.73 (brd, J = 5.6 Hz, 2H), 4.36 (br d, J = 3.4 Hz, 4H), 4.29 - 4.28 (m, 1H), 4.01 - 3.98 (m, 1H), 3.65 - 3.(m, 1H), 1.16 (d, J = 7.2 Hz, 3H) ppm 739 558.1 1H NMR (400 MHz, DMSO-d6) 5 = 9.53 - 9.52 (m, 1H), 9.03 (s, 1H), 8.57 - 8.47 (m, 2H), 8.32 - 8.18 (m, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.39 (s, 1H), 6.88 (s, 1H), 4.96 (s, 2H), 4.69 (d, J = 5.8 Hz, 2H), 4.37 - 4.30 (m, 2H), 4.25 - 4.17 (m, 4H), 3.69 - 3.62 (m, 2H), 2.03 - 1.97 (m, 1H), 0.90 - 0.85 (m, 4H) ppm 740 600.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.62 - 9.60 (m, 1H), 9.40 (s, 1H), 8.68 - 8.61 (m, 2H), 8.41 (d, J = 1.6 Hz, 1H), 8.27-8.24 (m, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.77 - 7.72 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 5.08 (s, 2H), 4.81 (brd, J = 5.Hz, 2H), 4.35 - 4.02 (m, 4H), 3.69 - 3.64 (m, 2H), 2.47 (br s, 2H), 1.33 -1.11 (m, 9H) ppm 741 550.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.58 (m, 1H), 9.08 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.36 (s, 1H), 8.29 - 8.24 (m, 3H), 7.82 - 7.69 (m, 2H), 7.49 (s, 1H), 7.(d, J = 1.8 Hz, 1H), 4.73 (br d, J = 5.7 Hz, 2H), 4.32 (s , 4H), 3.64 - 3.60 (m, 1H), 2.25 (s, 3H), 1.15 (d, J = 7.2 Hz, 3H) ppm 742 581.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.57 (m, 1H), 9.04 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.25-8.24 (m, 1H),8.18(d,J=9.2 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.62 - 7.60 (m, 1H), 7.46 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.48 - 6.11 (m, 1H), 4.97 (s, 2H), 4.72 (d, J = 5.Hz, 2H), 4.23 - 4.20 (m, 4H), 3.83 - 3.80 (m, 2H), 3.71 - 3.65 (m, 2H), 3.56 - 3.(m, 2H) ppm 743 516.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 -9.57 (m, 1H), 9.15 (d, J = 9.2 Hz, 1H), 9.08 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 9.2 Hz, 1H), 8.25 - 8.15 (m, 1H), 8.03 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 6.81 (d, J = 5.2 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.8 Hz, 2H), 4.34 -4.30 (m, 2H), 4.27 - 4.19 (m, 2H), 3.73 - 3.64 (m, 2H), 3.08 - 3.06 (m, 2H), 2.24 (s, 3H) ppm 744 545.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.40 (m, 1H), 8.97 (s, 1H), 8.51 (s, 1H), 8.49 (s, 1H), 8.29 - 8.20 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.15 (s, 1H), 4.98 (d, J = 6.8 Hz, 4H), 4.69 (d, J = 5.6 Hz, 2H), 4.28 - 4.14 (m, 6H), 3.67 (d, J = 4.0 Hz, 2H), 1.74 - 1.59 (m, 1H), 0.83 - 0.77 (m, 2H), 0.- 0.48 (m, 2H) ppm 294 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 745 619.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.62-9.53 (m, 1H), 9.00 (s, 1H), 8.52 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 6.73 (d, J = 8.Hz, 1H), 4.97 (s, 2H), 4.73 - 4.59 (m, 6H), 4.42 - 4.30 (m, 2H), 4.22 (s, 2H), 3.99 - 3.96 (m, 2H), 3.68 (s, 2H), 2.68 - 2.65 (m, 2H), 1.91-1.87 (m, 2H) ppm 746 572.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.57 (m, 1H), 9.07 (s, 1H), 8.53 (s, 1H), 8.47 (br s, 1H), 8.29 - 8.17 (m, 3H), 7.74 (d, J = 8.0 Hz, 1H), 7.56 - 7.46 (m, 2H), 6.48 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.74 (brd, J = 5.2 Hz, 2H), 4.23 (brd, J = 5.Hz, 2H), 4.14 (brt, J = 5.6 Hz, 2H), 4.00 (brd, J = 2.8 Hz, 1H), 3.68 (brd, J = 4.Hz, 2H), 2.76 (br t, J = 6.4 Hz, 2H), 2.01 -1.92 (m, 2H), 0.74 - 0.62 (m, 4H) ppm 747 615.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.55 - 9.54 (m, 1H), 8.99 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.34-8.29 (m, 1H), 8.24 - 8.22 (m, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.(d, J = 7.8 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.39 (s, 1H), 7.13 (d, J =8.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.68 - 6.65 (m, 1H), 4.97 (s, 2H), 4.70 (d, J = 5.8 Hz, 2H), 4.22 - 4.20 (m, 2H), 4.10 - 4.08 (m, 1H), 3.97 - 3.95 (m, 2H), 3.92 - 3.81 (m, 2H), 3.78 - 3.71 (m, 1H), 3.70 - 3.61 (m, 3H), 2.69 - 2.63 (m, 2H), 1.99 - 1.73 (m, 5H), 1.64 (s, 1H) ppm 748 571.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57- 9.54 (m, 1H), 9.01 (s, 1H), 8.52 (d, J = 1.2 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 7.28 (s, 1H), 4.97 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 4H), 3.78 - 3.60 (m, 2H), 3.39 - 3.35 (m, 2H), 2.46 - 2.41 (m, 1H), 2.25 (s, 3H), 0.93 - 0.79 (m, 2H), 0.66 - 0.55 (m, 2H) ppm 749 546.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.82 - 9.67 (m, 1H), 9.28 (d, J = 2.4 Hz, 1H), 9.02 (s, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.43 (s, 1H), 8.24 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 6.80 - 6.71 (m, 2H), 5.10 - 4.99 (m, 2H), 4.72 (brd, J = 6.0 Hz, 2H), 4.35 -4.33 (m, 1H), 4.30 -4.17 (m, 4H), 4.12 - 4.03 (m, 1H), 3.83 -3.82 (m, 1H), 2.26 (s, 3H), 1.21 (d, J = 7.0 Hz, 3H) ppm 750 563.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.54-9.53 (m, 1H), 9.02 (s, 1H), 8.51 (d, J = 1.Hz, 1H), 8.28 - 8.17 (m, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 7.(s, 1H), 6.77 - 6.75 (m, 1H), 6.67 -6.65 (m, 1H), 4.97 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.26 - 4.19 (m, 2H), 4.06 - 3.99 (m, 2H), 3.82 (s, 3H), 3.72 - 3.62 (m, 2H), 2.- 2.58 (m, 2H), 1.92 -1.81 (m, 2H) ppm 751 576.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.59- 9.56 (m, 1H), 9.11 (s, 1H), 8.53 (d, J =1.6 Hz, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.26 - 8.24 (m, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.35 (d, J = 10.0 Hz, 1H), 4.98 (s, 2H), 4.(d, J = 5.6 Hz, 2H), 4.32 - 4.28 (m, 4H), 4.26 - 4.21 (m, 2H), 3.71 - 3.65 (m, 2H), 2.23 - 2.15 (m, 1H), 0.99 - 0.91 (m, 2H), 0.90 - 0.84 (m, 2H) ppm 295 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 752 544.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.56 (m, 1H), 9.Q8 (s, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.26- 8.25 (m, 1H), 8,18 (d, J = 9.2 Hz, 1H), 8.12 - 8.11 (m, 1H), 7.(d, J = 9.2 Hz, 1H), 7.82 - 7.81 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.09 - 7.08 (m, 1H), 4.99 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.26 - 4.19 (m, 2H), 4.19 - 4.(m, 2H), 3.71 - 3.66 (m, 2H), 1.87 - 1.79 (m, 2H), 1.31 (s, 6H) ppm 753 572.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57- 9.56 (m, 1H), 9.08 (s, 1H), 8.53 (d, J = 1.Hz, 1H), 8.32 - 8.22 (m, 3H), 7.80 (d, J = 1.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.(s, 1H), 7.27 (d, J = 1.8 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.8 Hz, 2H), 4.33 (s, 4H), 4.27 - 4.18 (m, 2H), 3.71 - 3.65 (m, 2H), 3.50 -3.30 (m, 1H), 2.28 -2.10 (m, 2H), 2.17 - 2.06 (m, 2H), 2.03 - 1.92 (m, 1H), 1.87 - 1.80 (m, 1H) ppm 754 587.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.56 - 9.54 (m, 1H), 9.00 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.26 - 8.23 (m, 1H), 8.18 (s, 2H), 8.15 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.53 - 7.25 (m, 2H), 6.56 (d, J = 2.4 Hz, 1H), 4.98 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.36 - 4.18 (m, 6H), 3.73 - 3.65 (m, 2H), 3.24 - 3.21 (m, 4H), 2.03 - 1.86 (m, 4H) ppm 755 558.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 - 9.56 (m, 1H), 9.16 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.25 - 8.22 (m, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 7.6 Hz, 2H), 4.97 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.32 - 4.30 (m, 2H), 4.26 - 4.20 (m, 2H), 4.18 - 4.(m, 2H), 3.69 - 3.65 (m, 2H), 2.00 - 1.89 (m, 1H), 0.85 - 0.75 (m, 4H) ppm 756 597.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57- 9.55 (m, 1H), 9.01 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.43 (s, 1H), 7.(d, J = 2.0 Hz, 1H), 4.98 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.24 - 4.21 (m, 4H), 3.72 - 3.65 (m, 2H), 3.37 (d, J = 5.6 Hz, 2H), 2.47 - 2.45 (m, 1H), 1.96 - 1.86 (m, 1H), 1.- 0.92 (m, 2H), 0.89 - 0.81 (m, 2H), 0.74 - 0.66 (m, 2H), 0.63 - 0.54 (m, 2H) ppm 757 593.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.55- 9.54 (m, 1H), 9.12-9.03 (m, 1H), 8.(d, J = 1.8 Hz, 1H), 8.40 (brs, 1H), 8.32 (d, J = 9.2 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.38 (s, 1H), 7.13-7.12 (m, 1H), 6.72 - 6.70 (m, 1H), 4.(s, 2H), 4.71 (d, J = 5.8 Hz, 2H), 4.28 - 4.15 (m, 6H), 3.69 - 3.64 (m, 2H), 1.77 - 1.68 (m, 1H), 0.92 - 0.85 (m, 2H), 0.75 - 0.65 (m, 2H) ppm 758 623.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.54 (m, 1H), 9.02 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.40- 8.35 (m, 1H), 8.26-8.24 (m, 1H), 8.23-8.17 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.50 - 7.40 (m, 2H), 6.73 (d, J = 2.8 Hz, 1H), 4.98 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.32 - 4.29 (m, 4H), 4.26 - 4.18 (m, 2H), 3.75 - 3.66 (m, 4H), 3.51 - 3.47 (m, 2H), 2.56 - 2.53 (m, 2H) ppm 296 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 759 615.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 - 9.55(m, 1H), 8.99 (s, 1H), 8.52 (d, J = 2.Hz, 1H), 8.26 - 8.23 (m, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.(d, J = 9.2 Hz, 1H), 7.39 (s, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.27 - 4.18 (m, 2H), 3.98 - 3.97 (m, 2H), 3.90 - 3.84 (m, 1H), 3.83 - 3.77 (m, 1H), 3.77 - 3.71 (m, 2H), 3.70 - 3.66 (m, 2H), 3.65 - 3.58 (m, 1H), 3.49 (d, J = 8.8 Hz, 1H), 2.70 - 2.63 (m, 2H), 2.62 - 2.56 (m, 1H), 2.02 - 1.93 (m, 1H), 1.93 - 1.85 (m, 2H), 1.66 - 1.55 (m, 1H) ppm 760 575.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.49 (m, 1H), 9.10 - 9.00 (m, 1H), 8.52 - 8.48 (m, 1H), 8.34 - 8.26 (m, 1H), 8.26 - 8.20 (m, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.- 7.37 (m, 1H), 7.13 - 7.03 (m, 1H), 6.80 - 6.55 (m, 2H), 4.96 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.22 (s, 6H), 3.71 - 3.63 (m, 2H), 2.00 - 1.85 (m, 1H), 0.98 - 0.85 (m, 2H), 0.73 - 0.61 (m, 2H) ppm 761 546.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.56 - 9.53 (m, 1H), 9.03 (s, 1H), 8.51 (d, J =1.6 Hz, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 8.26 - 8.22 (m, 2H), 8.03 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.38 (s, 1H), 4.97 (s, 2H), 4.70 (d, J = 6.0 Hz, 2H), 4.28 - 4.19 (m, 2H), 4.09 - 4.00 (m, 2H), 3.92 (s, 3H), 3.70 - 3.65 (m, 2H), 2.- 2.65 (m, 2H), 1.96 - 1.84 (m, 2H) ppm 762 527.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 -9.58 (m, 1H), 9.28 (s, 1H), 8.52 (d, J = 1.Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.19 -8.09 (m, 1H), 7.(d, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H),7.14 -6.90 (m, 1H), 4.97 (s, 2H), 4.78 (d, J = 5.8 Hz, 2H), 4.22- 4.10(m, 2H), 3.71 - 3.64 (m, 2H), 2.85 - 2.75 (m, 1H), 2.72 - 2.61 (m, 1H), 2.27 (d, J = 8.6 Hz, 1H), 2.- 2.05 (m, 1H), 2.01 -1.90 (m, 1H), 1.84 - 1.77 (m, 1H), 1.48 - 1.40 (m, 1H) ppm 763 561.4 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.57 (m, 1H), 9.01 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.20 (s, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.42 (s, 1H), 6.77 (d, J = 2.8 Hz, 1H), 4.97 (s, 2H), 4.71 (d, J = 5.Hz, 2H), 4.32 (d, J = 4.8 Hz, 2H), 4.30 - 4.25 (m, 2H), 4.25 - 4.20 (m, 2H), 3.72 - 3.65 (m, 2H), 2.89 (s, 6H) ppm 764 549.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 - 9.47 (m, 1H), 9.06 (s, 1H), 8.50 (d, J =1.6 Hz, 1H), 8.30 (d, J = 9.0 Hz, 1H), 8.26 - 8.20 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H),7.41 (s, 1H), 7.09 -6.90 (m, 1H), 6.76 - 6.70 (m, 1H), 6.69 - 6.63 (m, 1H),4.97 (s, 2H), 4.71 (br d, J = 5.4 Hz, 2H), 4.33 - 4.14 (m, 7H), 3.76 - 3.61 (m, 2H),2.28 (s, 3H) ppm 765 575.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.56-9.55 (m, 1H), 9.06 (s, 1H), 8.51 (d, J = 1.Hz, 1H), 8.44 - 8.39 (m, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.(d, J = 7.8 Hz, 1H), 7.41 (s, 1H), 7.07-6.90 (m, 1H), 6.81 - 6.36 (m, 2H), 4.97 (s, 2H), 4.71 (br d, J = 5.6 Hz, 2H), 4.23 (br s, 6H), 3.75 - 3.60 (m, 2H), 1.99 - 1.82 (m, 1H), 1.03 - 0.86 (m, 2H), 0.75 - 0.61 (m, 2H) ppm 297 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 766 584.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.59 (m, 1H), 9.Q9 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.33-8.16 (m,3H), 7.81 (d, J = 4.8 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 6.83 (d, J = 4.8 Hz, 1H), 4.98 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.36 (d, J = 4.8 Hz, 2H), 4.32 (d, J = 4.8 Hz, 2H), 4.26 - 4.19 (m, 2H), 3.74 - 3.63 (m, 2H), 2.58 (s, 1H), 2.15 (s, 6H) ppm 767 552.1 1H NMR (400 MHz, METHANOL-d4) 5 = 9.10 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.- 8.43 (m, 1H), 8.35 - 8.31 (m, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.21- 8.19 (m, 1H), 8.07 (d, J = 9.2 Hz, 2H), 7.71 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.18 - 7.17 (m, 1H), 5.05 (s, 2H), 4.98 - 4.95 (m, 2H), 4.44 - 4.39 (m, 2H), 4.36 - 4.32 (m, 2H), 3.54 - 3.51 (m, 2H), 2.64 - 2.50 (m, 2H) ppm 768 546.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59-9.58 (m, 1H), 9.13 (s, 1H), 8.51 (d, J = 1.Hz, 1H), 8.39 (s, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.92 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.49 (s, 1H), 6.73 (s, 1H), 4.97 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.28 - 4.15 (m, 2H), 3.96 -3.90 (m, 2H), 3.(s, 3H), 3.70 - 3.65 (m, 2H), 2.75 - 2.67 (m, 2H), 2.01 - 1.87 (m, 2H) ppm 769 588.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.83 - 9.69 (m, 1H), 9.35 - 9.27 (m, 2H), 8.(d, J = 2.2 Hz, 1H), 8.61 (s, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), 7.70 - 7.60 (m, 1H), 7.45 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.14 - 4.96 (m, 2H), 4.79 (br d, J = 5.4 Hz, 2H), 4.42 - 4.26 (m, 3H), 4.09 -3.99 (m, 1H), 3.81 (brd, J = 2.8 Hz,1H), 3.71 - 3.62 (m, 2H), 3.38 (brs, 2H), 1.25-1.17 (m, 9H) ppm 770 550.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59- 9.56 (m, 1H), 9.10 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.29 (s, 2H), 8.26 - 8.25 (m, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.37 (d, J = 9.6 Hz, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.34 (s, 4H), 4.27 - 4.21 (m, 2H), 3.71 - 3.66 (m, 2H), 2.34 (d, J = 2.8 Hz, 3H) ppm 771 586.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 - 9.54 (m, 1H), 9.04 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.21 (s, 1H), 8.15 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H). 7.73 (d, J = 8.0 Hz, 1H), 7.45 (s, 1H), 6.77 (s, 1H), 4.97 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.22 - 4.21 (m, 2H), 4.12 - 4.05 (m, 2H), 3.87 (s, 3H), 3.71 - 3.65 (m, 2H), 2.61 - 2.58 (m, 2H), 2.04 - 1.94 (m, 1H), 1.93 - 1.82 (m, 2H), 0.89 - 0.75 (m, 4H) ppm 772 574.1 1H NMR (400 MHz, METHANOL-d4) 6 = 9.33 (s, 1H), 8.70 - 8.58 (m, 3H), 8.48 (d, J = 8.4 Hz, 1H), 8.23 - 8.20 (m, 1H), 7.98 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 4.39 - 4.32 (m, 2H), 4.30 - 4.12 (m, 2H), 3.77 - 3.74 (m, 2H), 3.56 - 3.51 (m, 2H), 3.44 (s, 3H), 3.25 - 3.24 (m, 2H), 3.15 - 3.14 (m, 4H) ppm 298 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 773 587.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.66-9.57 (m, 1H), 9.10 (s, 1H), 8.43 (d, J = 4.4 Hz, 1H), 8.40- 8.30 (m, 2H), 8.15-8.13 (m, 1H), 7.44 (s, 1H), 7.20-7.11 (m, 1H), 7.10 - 7.08 (m, 1H), 7.01 - 6.97 (m, 1H), 5.02 (s, 2H), 4.71 (d, J = 5.2 Hz, 2H), 4.33 - 4.17 (m, 6H), 3.79 - 3.72 (m, 2H) ppm 774 565.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.56 - 9.54 (m, 1H), 9.05 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 9.2 Hz, 1H), 8.24 - 8.22 (m,1 H), 7.72 (d, J = 7.6 Hz, 1H), 7.40 (s, 1H), 7.08 - 7.05 (m, 1H), 6.59 - 6.55 (m, 1H), 6.44 - 6.43 (m, 1H), 4.97 (s, 2H), 4.71 (d, J = 6.0 Hz, 2H), 4.28 - 4.19 (m, 6H), 3.75 (s, 3H), 3.69 - 3.65 (m, 2H) ppm 775 558.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.70 - 9.67 (m, 1H), 8.54 - 8.43 (m, 2H), 8.23 - 821 (m. 1H), 7.83 - 7.69 (m, 2H), 7.63 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.75 - 6.(m, 2H), 5.06 - 4.88 (m, 4H), 4.34 - 4.14 (m, 6H), 3.73 - 3.61 (m, 2H), 1.95 - 1.(m, 1H), 0.99 - 0.87 (m, 2H), 0.71 - 0.58 (m, 2H) ppm 776 547.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.58 - 9.55 (m, 1H), 9.06 (s, 1H), 8.52 (d, J =1.6 Hz, 1H), 8.35 (s, 1H), 8.32 - 8.18 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.62 (d, J =9.2 Hz, 1H), 7.43 (s, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.68 - 6.65 (m, 1H), 4.98 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.24 - 4.22 (m, 4H), 4.20 - 4.(m, 2H), 3.70 - 3.67 (m, 5H) ppm 777 568.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.55 (m, 1H), 9.11 (s, 1H), 8.88 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.27 (s, 1H), 8.24 - 8.22 (m, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 7.01 - 6.72 (m, 1H), 4.97 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.44 - 4.42 (m, 2H), 4.27 - 4.(m, 4H), 3.70 - 3.65 (m, 2H) ppm 778 566.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60- 9.57 (m, 1H), 9.12 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.46 - 8.40 (m, 1H), 8.32 (s, 2H), 8.26 - 8.24 (m, 1H), 7.73 (d, J = 8.Hz, 1H), 7.49 (d, J = 9.6 Hz, 2H), 4.98 (s, 2H), 4.74 (brd, J = 6.0 Hz, 2H), 4.33 (s, 4H), 4.26 - 4.19 (m, 2H), 3.71 - 3.65 (m, 2H), 2.42 (s, 3H) ppm 779 590.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.67 - 9.55 (m, 1H), 9.40 (s, 1H), 8.72 - 8.57 (m, 2H), 8.50 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.(s, 1H), 7.78 - 7.70 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 5.11 - 4.89 (m, 1H), 4.81 (d, J = 5.6 Hz, 2H), 4.31 (d, J = 11.6 Hz, 2H), 3.72 - 3.60 (m, 3H), 3.58 - 3.45 (m, 3H), 2.56 (d, J = 4.0 Hz, 2H), 2.47 - 2.39 (m, 2H), 1.21 (d, J = 6.0 Hz, 6H) ppm 780 557.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.60 (m, 1H), 9.20 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.26-8.24 (m, 1H), 8.19 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 4.97 (s, 2H), 4.76 (d, J = 6.0 Hz, 2H), 4.29 - 4.18 (m, 2H), 4.15 - 4.05 (m, 2H), 3.71 - 3.66 (m, 2H), 2.76 - 2.73 (m, 2H), 2.02 - 1.92 (m, 3H), 0.94 - 0.80 (m, 4H) ppm 299 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 781 586.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64-9.53 (m, 1H), 9.14 (s, 1H), 8.53 (d, J =1.6 Hz, 1H), 8.41 (br s, 1H), 8.38 - 8.33 (m, 1H), 8.31 - 8.23 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 10.4 Hz, 1H), 7.52 (s, 1H), 7.19-6.86 (m, 1H), 5.04-4.(m, 2H), 4.78 - 4.71 (m, 2H), 4.45 - 4.36 (m, 4H), 4.27 - 4.19 (m, 2H), 3.71 - 3.(m, 2H) ppm 782 587.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57-9.56 (m, 1H), 9.02 (s, 1H), 8.53 (d, J = 1.Hz, 1H), 8.28 - 8.18 (m, 3H), 7.77 - 7.69 (m, 2H), 7.43 (s, 1H), 6.96 (d, J = 2.4 Hz, 1H), 4.98 (s, 2H), 4.71 (d, J = 5.8 Hz, 2H), 4.38 - 4.26 (m, 4H), 4.23 (d, J = 5.8 Hz, 2H), 3.71 - 3.65 (m, 2H), 2.92 (s, 3H), 2.39 -2.30 (m, 1H), 0.91 - 0.78 (m, 2H), 0.- 0.47 (m, 2H) ppm 783 564.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.56-9.55 (m, 1H), 9.12 (s, 1H), 8.50 (d, J = 1.Hz, 1H), 8.38 (brs, 1H), 8.32 (d, J = 9.0 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.81 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.21 (d, J = 9.0 Hz, 1H),4.97 (s, 2H), 4.72 (d, J = 5.8 Hz, 2H), 4.25 - 4.20 (m, 2H), 4.00 (br t, J = 6.1 Hz, 2H), 3.91 (s, 3H), 3.69 - 3.65 (m, 2H), 2.72-2.70 (m, 2H), 1.93 -1.90 (m,2H) ppm 784 572.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.56-9.55 (m, 1H), 9.06 (s, 1H), 8.51 (d, J-1.Hz, 1H), 8.33-8.19 (m,3H), 7.72 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 4.97 (s, 2H), 4.72 (d, J = 5.8 Hz, 2H), 4.38 - 4.27 (m, 4H), 4.22-4.10 (m, 2H), 3.71 - 3.63 (m, 2H), 2.31 - 2.23 (m, 3H), 1.89 - 1.78 (m, 1H), 0.95 - 0.85 (m, 2H), 0.67 - 0.59 (m, 2H) ppm 785 557.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60- 9.59 (m, 1H), 9.12 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.43 (s, 1H), 8.32 - 8.22 (m, 2H), 8.17 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 4.97 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 4.18 - 4.10 (m, 2H), 3.74 - 3.63 (m, 2H), 2.95 - 2.91 (m, 2H), 2.12 - 1.99 (m, 3H), 0.98 - 0.89 (m, 2H), 0.80 - 0.78 (m, 2H) ppm 786 556.3 1H NMR (400 MHz, DMSO-d6) 6 9.53 (s, 1H), 9.15 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.33 (s, 1H), 8.27 (dd, J = 7.8, 1.9 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.(d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.9, 2.3 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J = 2.2 Hz, 1H), 6.87-6.78 (m, 2H), 6.59 (dd, J = 8.4, 2.1 Hz, 1H), 5.01 (s, 2H), 4.73 (d, J = 5.7 Hz, 2H), 4.30 - 4.22 (m, 4H), 3.89 - 3.82 (m, 2H), 3.73 - 3.66 (m, 2H), 1.(ddd, J = 13.4, 8.5, 5.0 Hz, 1H), 0.92 - 0.78 (m, 2H), 0.54 - 0.45 (m, 2H). 787 557.2 1H NMR (400 MHz, DMSO-d6) 6 9.54 (d, J = 6.0 Hz, 1H), 9.16 (s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.28 (dd, J = 7.8, 1.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.90 (dd, J = 9.1,2.1 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.62 (d, J = 2.3 Hz, 2H), 6.90 (d, J = 2.1 Hz, 1H), 6.53 (s, 1H), 5.01 (s, 2H), 4.75 (d, J = 5.8 Hz, 2H), 4.(t, J = 4.5 Hz, 2H), 4.30 - 4.23 (m, 2H), 4.04 - 3.97 (m, 2H), 3.73 - 3.66 (m, 2H), 1.88 (t, J = 8.5 Hz, 1H), 0.96 - 0.88 (m, 2H), 0.71 - 0.63 (m, 2H). 300 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 788 556.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.33 (s, 1H), 8.70 - 8.65 (m, 1H), 8.64 - 8.58 (m, 2H), 8.41 (d, J = 8.0 Hz, 1H), 8.23 - 8.20 (m, 1H), 7.98 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 5.05 (s, 2H), 4.94 (s, 2H), 4.38 - 4.31 (m, 2H), 4.05 (s, 2H), 3.55 - 3.51 (m, 2H), 3.09 - 3.08 (m, 2H), 3.03 - 3.02 (m, 2H), 2.07 - 2.01 (m, 1H), 0.71 - 0.65 (m, 2H), 0.64 - 0.58 (m, 2H) ppm 789 580.3 1H NMR (400 MHz, DMSO-d6) 5 = 13.26 - 12.32 (m, 1H), 9.52 - 9.50 (m, 1H), 9.(s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.32 - 8.26 (m, 1H), 8.28 - 8.22 (m, 1H), 8.08 - 7.85 (m, 3H), 7.71 (d, J = 8.0 Hz, 1H), 7.57 - 7.50 (m, 2H), 7.46 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.28 - 7.26 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.96 (s, 2H), 4.68 (br d, J = 5.6 Hz, 2H), 4.24 -4.19 (m, 2H), 3.73 - 3.70 (m, 2H), 3.68 - 3.64 (m, 2H), 2.78 - 2.75 (m, 2H), 2.00 - 1.93 (m, 2H) ppm 790 560.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.54-9.50 (m, 1H), 9.07 (s, 1H), 8.51 (d, J = 1.Hz, 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.95 - 7.89 (m, 1H), 7.88 - 7.82 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.52 (s, 2H), 7.38 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.(s, 2H), 4.69 (d, J = 5.8 Hz, 2H), 4.34 - 4.18 (m, 4H), 3.97 - 3.89 (m, 2H), 3.71 - 3.62 (m, 2H), 2.82 (s, 6H) ppm 791 621.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.84-9.83 (m, 1H), 9.43 (d, J = 2.0 Hz, 1H), 9.(s, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.70 - 8.60 (m, 2H), 8.36 (br s, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.87 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz,1H), 4.84 (d, J = 5.6 Hz, 2H), 4.32 (br d, J = 11.0 Hz, 2H), 3.81 - 3.73 (m, 1H), 3.- 3.63 (m, 3H), 3.53 (brdd, J = 13.6 Hz, 1H), 2.52 - 2.52 (m, 3H), 2.45 - 2.41 (m, 1H), 1.39 - 1.28 (m, 1H), 1.21 (d, J = 6.2 Hz, 6H) ppm 792 559.32 1H NMR (400 MHz, DMSO-d6) 6 9.51 (t, J = 5.9 Hz, 1H), 8.95 (s, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.24 (dd, J=7.8, 1.9 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.72 (d, 7.8Hz, 1H), 7.36 (s, 1H), 7.31 (d, J = 9.2 Hz, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 5.99 (s, 2H), 4.97 (s, 2H), 4.69 (d, J = 5.8 Hz, 2H), 4.26 -4.19 (m, 2H), 3.95 (t, J = 6.5 Hz, 2H), 3.71 - 3.64 (m, 2H), 2.61 (t, J = 6.6 Hz, 2H), 1.87 (p, J = 6.5 Hz, 2H). 793 573.32 1H NMR (400 MHz, DMSO-d6) 6 9.52 (t, J = 5.9 Hz, 1H), 8.94 (s, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.24 (dd, J= 7.8, 1.9 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.72 (d, J=7.Hz, 1H), 7.42 - 7.30 (m, 2H), 6.84 (s, 1H), 6.75 (s, 1H), 4.97 (s, 2H), 4.69 (d, J = 5.8 Hz, 2H), 4.22 (d, J = 5.3 Hz, 5H), 3.94 (t, J = 6.4 Hz, 2H), 3.75 - 3.62 (m, 2H), 2.60 (t, J = 6.6 Hz, 2H), 1.87 (p, J = 6.5 Hz, 2H). 794 613.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.56- 9.53 (m, 1H), 9.11 (s, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.44 (d, J = 1.2 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.23 - 8.21 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.24-7.23 (m, 1H), 6.95 (d, J = 1.6 Hz, 1H), 4.97 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.48 (s, 2H), 4.31 - 4.18 (m, 6H), 3.71 - 3.(m, 2H), 3.36 (s, 3H) ppm 301 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 795 612.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 - 9.58 (m, 1H), 9.13 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.Hz, 1H), 4.97 (s, 2H), 4.74 (d, J = 6.0 Hz, 2H), 4.52 - 4.33 (m, 3H), 4.26 - 4.15 (m, 3H), 3.72 - 3.64 (m, 2H), 2.63 - 2.56 (m, 2H) ppm 796 579.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.55 - 9.45 (m, 1H), 9.07 (s, 1H), 8.50 (d, J =1.6 Hz, 1H), 8.42 (brs, 1H), 8.31 (d, J = 9.2 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.73 -7.70 (m, 1H), 7.41 (s, 1H), 7.12 (d, J = 9.2 Hz, 1H), 6.85 -6.77 (m,2H), 4.96 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.38 (s, 2H), 4.27 - 4.20 (m, 6H), 3.69 -3.65 (m, 2H), 3.30 (s, 3H) ppm 797 590.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.19 (s, 1H), 8.57 - 8.50 (m, 2H), 8.50 - 8.43 (m, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.61 - 7.50 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H), 6.48 (d, J = 8.2 Hz, 1H), 4.95 (s, 2H), 4.(s, 2H), 4.80 (brs, 1H), 4.74 (d, J = 8.4 Hz, 1H), 4.66 (d, J = 19.2 Hz, 2H), 4.26 - 4.22 (m, 2H), 4.19-4.00 (m, 2H), 3.96 (d, J = 8.4 Hz, 2H), 3.47 - 3.40 (m, 2H), 3.- 3.23 (m, 1H) ppm 798 602.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.54-9.51 (m, 1H), 9.09 (s, 1H), 8.51 (d, J =1.6 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.88 - 7.83 (m, 1H), 7.(d, J = 8.0 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.50 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 2.Hz, 1H), 4.97 (s, 2H), 4.70 (d, J = 5.6 Hz, 2H), 4.36 - 4.27 (m, 2H), 4.26 - 4.18 (m, 2H), 3.99 - 3.91 (m, 2H), 3.76 - 3.69 (m, 4H), 3.68 - 3.63 (m, 2H), 3.07 - 3.01 (m, 4H) ppm 799 567.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.62 - 9.44 (m, 1H), 9.18 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.29 - 8.20 (m, 1H), 8.10 - 7.97 (m, 1H), 7.91 (d, J = 9.2 Hz,1H), 7.81 - 7.67 (m, 2H), 7.62 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.70 - 6.45 (m, 1H), 4.97 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.50 -4.35 (m, 2H), 4.29-4.(m, 2H), 4.09 - 3.99 (m, 2H), 3.73 - 3.59 (m, 2H) ppm 800 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.53 - 9.44 (m, 1H), 9.39 - 9.30 (m, 1H), 8.(d, J = 1.6 Hz, 1H), 8.26 - 8.18 (m, 1H), 7.97 (d, J = 1.2 Hz, 2H), 7.76 - 7.69 (m, 1H), 7.66 - 7.58 (m, 2H), 6.90 (d, J = 2.0 Hz, 1H), 4.97 (s, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.37 - 4.29 (m, 2H), 4.24 - 4.20 (m, 2H), 4.05 - 3.98 (m, 2H), 3.69 - 3.64 (m, 2H), 1.92 - 1.80 (m, 1H), 0.94 - 0.86 (m, 2H), 0.69 - 0.60 (m, 2H) ppm 801 558.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60-9.55 (m, 1H), 9.29 (d, J = 2.4 Hz, 1H), 9.(s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.40 (brs, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.60 (d, J = 2.0Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 4.97 (s, 2H), 4.75 (d, J = 5.6 Hz, 2H), 4.41 - 4.(m, 2H), 4.25 - 4.20 (m, 2H), 4.00 - 3.94 (m, 2H), 3.69 - 3.64 (m, 2H), 1.89 - 1.(m, 1H), 0.93 - 0.86 (m, 2H), 0.68 - 0.61 (m, 2H) ppm 302 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 802 564.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59- 9.58 (m, 1H), 9.12 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.26 -8.18 (m, 2H), 8.15 (d, J = 3.6 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 4.98 (s, 2H), 4.75 (d, J = 5.6 Hz, 2H), 4.26 - 4.20 (m, 2H), 4.17 - 4.12 (m, 2H), 4.09 (d, J = 4.0 Hz, 3H), 3.70 - 3.66 (m, 2H), 2.- 2.73 (m, 2H), 1.96 - 1.88 (m, 2H) ppm 803 561.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.49 (m, 1H), 8.99 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.28-8.19 (m, 3H), 7.72 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.36 (s, 1H), 6.16 (s, 1H), 5.00 - 4.94 (m, 2H), 4.73 - 4.64 (m, 2H), 4.31 - 4.19 (m, 6H), 3.73 - 3.62 (m, 2H), 2.98 (s, 6H) ppm 804 576.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.60- 9.57 (m, 1H), 9.13 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.45 (s, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.26 - 8.23 (m, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.05 (d, J =11.2 Hz, 1H), 4.(s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.38 - 4.34 (m, 2H), 4.33 - 4.28 (m, 2H), 4.25 - 4.20 (m, 2H), 3.71 - 3.65 (m, 2H), 2.03 - 1.97 (m, 1H), 0.90 - 0.87 (m, 2H), 0.83 - 0.78 (m, 2H) ppm 805 593.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.54-9.51 (m, 1H), 9.10 (s, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.42 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.23 - 8.21 (m, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.44 (s, 1H), 7.26 - 7.22 (m, 1H), 6.43 - 6.41 (m, 1H), 4.97 (s, 2H), 4.(d, J = 5.6 Hz, 2H), 4.30 - 4.14 (m, 6H), 3.70 - 3.59 (m, 2H), 2.08 - 2.02 (m, 1H), 1.02 - 0.95 (m, 2H), 0.79 - 0.74 (m, 2H) ppm 806 530.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 - 9.54(m, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.84 - 7.51 (m, 3H), 4.98 (s, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.28 - 4.(m, 2H), 4.06 (s, 3H), 3.73 - 3.65 (m, 2H) ppm 807 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.61 -9.58 (m, 1H), 9.14 (s, 1H), 8.53 (d, J = 1.Hz, 1H), 8.35 (s, 2H), 8.26 -8.16 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.04 - 6.66 (m, 1H), 4.75 (d, J = 5.7 Hz, 2H), 4.39 (brd, J = 8.6 Hz, 4H) ppm 808 491.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 (brd, J = 5.6 Hz, 1H), 9.40 (s, 1H), 8.61 (d, J = 8.6 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.36 - 8.24 (m, 3H), 8.18 (d, J = 8.6 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.19-7.10 (m, 1H), 4.97 (s, 2H), 4.82 (br d, J = 5.6 Hz, 2H), 4.26 - 4.19 (m, 2H), 3.98 (s, 3H), 3.71 - 3.64 (m, 2H) ppm 809 572.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60 - 9.57 (m, 1H), 9.10 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.42 (br s, 1H), 8.30 (d, J = 9.2 Hz, 1H), 8.26 - 8.24 (m, 1H), 8.22 - 8.18 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.48 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.(d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.73 (brd, J = 5.6 Hz, 2H), 4.33 - 4.20 (m, 6H), 3.73 - 3.65 (m, 2H), 1.81 - 1.64 (m, 1H), 1.20 - 1.08 (m, 4H), 0.99 - 0.97 (m, 1H), 0.73 - 0.63 (m, 1H) ppm 303 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 810 572.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60- 9.57 (m, 1H), 9.10 (s, 1H), 8.52 (s, 1H), 8.42 (brs, 1H), 8.30 (d, J = 9.2 Hz, 1H), 8.25 (brd, J = 7.6 Hz, 1H), 8.22 - 8.17 (m, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.48 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.Hz, 1H), 4.97 (s, 2H), 4.73 (br d, J = 5.6 Hz, 2H), 4.28 (br s, 4H), 4.25 - 4.20 (m, 2H), 3.71 - 3.66 (m, 2H), 1.79 - 1.68 (m, 1H), 1.20 - 1.08 (m, 4H), 1.02 - 0.93 (m, 1H), 0.68-0.66 (m, 1H) ppm 811 558.3 1H NMR (400 MHz, METHANOL-d4) 6 = 9.26 (s, 1H), 9.22 (s, 1H), 8.59 (d, J = 2.Hz, 1H), 8.53 - 8.44 (m, 1H), 8.22 - 8.12 (m, 2H), 7.72 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.04 (s, 2H), 4.81 (s, 2H), 4.- 4.30 (m, 6H), 3.54 - 3.51 (m, 2H), 1.96 - 1.85 (m, 1H), 1.02 - 0.92 (m, 2H), 0.74 - 0.63 (m, 2H) ppm 812 530.2 1H NMR (400 MHz, DMSO-d6) 5 = 9.64 - 9.61 (m, 1H), 9.27 (s, 1H), 8.62 - 8.48 (m, 3H), 8.37 (s, 1H), 8.26 - 8.24 (m, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.69 - 7.25 (m, 2H), 4.98 (s, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.26 - 4.20 (m, 2H), 3.83 (s, 3H), 3.69 - 3.66 (m, 2H) ppm 813 576.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 -9.45 (m, 1H), 9.07 (s, 1H), 8.53 - 8.46 (m, 2H), 8.32 (d, J = 9.0 Hz, 1H), 8.23 -8.20 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.42 (s, 1H), 4.97 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.43 -4.40 (m, 2H), 4.31 - 4.14 (m, 4H), 3.71 - 3.64 (m, 2H), 2.23 -2.20 (m, 1H), 1.05 - 0.89 (m, 4H) ppm 814 571.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62- 9.50 (m, 1H), 9.05 (brs, 1H), 8.52 (s,1H), 8.36 - 8.01 (m, 2H), 7.85 - 7.69 (m, 3H), 7.47 (br s, 1H), 6.17 (br d, J = 6.0 Hz,1H), 4.97 (s, 2H), 4.72 (brd,J- 5.6 Hz, 2H), 4.28 - 4.00 (m, 8H), 3.73 - 3.66 (m, 2H), 2.69 (br s, 2H), 2.31 - 2.22 (m, 2H), 1.93 - 1.82 (m, 2H) ppm 815 530.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.64 -9.60 (m, 1H), 9.37 (s, 1H), 8.63 - 8.49 (m, 2H), 8.41 (brs, 1H), 8.25 (brd, J = 7.8 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.86 - 7.(m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.46 (brt, J = 7.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.08 -7.00 (m, 1H), 4.97 (s, 2H), 4.81 (brd, J = 5.6 Hz, 2H), 4.29 - 4.12 (m, 2H), 3.96 (d, J = 6.8 Hz, 2H), 3.72 - 3.63 (m, 2H), 1.29 -1.14 (m, 1H), 0.52 (brd, J = 6.8 Hz, 2H), 0.31 (brd, J = 5.0 Hz, 2H) ppm 816 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.62-9.51 (m, 1H), 9.04 (s, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.30-8.21 (m, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 6.97 (s, 1H), 4.97 (s, 2H), 4.72 (d, J = 5.6 Hz, 2H), 4.32 (s, 2H), 4.32 - 4.21 (m, 2H), 4.18 - 4.09 (m, 2H), 3.71 - 3.65 (m, 2H), 3.- 3.29 (m, 3H), 2.75 - 2.70 (m, 2H), 2.26 (s, 3H), 2.00 - 1.92 (m, 2H) ppm 304 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 817 637.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.63 - 9.53 (m, 1H), 9.04 (s, 1H), 8.55 - 8.50 (m, 1H), 8.30 - 8.21 (m, 3H), 7.77 - 7.71 (m, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.44 (s, 1H), 6.94 (d, J = 2.4 Hz, 1H), 5.02 - 4.94 (m, 2H), 4.75 - 4.70 (m, 2H), 4.37 - 4.28 (m, 4H), 4.26 - 4.20 (m, 2H), 3.97 - 3.83 (m, 1H), 3.73 - 3.63 (m, 2H), 3.05 - 2.90 (m, 2H), 2.80 (s, 3H), 2.68 - 2.60 (m, 2H) ppm 818 574.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.53 - 9.50 (m, 1H), 9.14 (s, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.35 (s, 2H), 8.26 - 8.24 (m, 1H), 7.50 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.02 -6.70 (m, 1H), 4.73 (d, J = 5.6 Hz, 2H), 4.45 - 4.34 (m, 4H) ppm 819 601.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.60 - 9.48 (m, 1H), 9.05 - 8.95 (m, 1H), 8.56 - 8.48 (m, 1H), 8.44 - 8.38 (m, 1H), 8.28 - 8.15 (m, 3H), 7.73 (d, J = 7.8 Hz, 1H), 7.(d, J = 2.4 Hz, 1H), 7.45 - 7.40 (m, 1H), 6.83 - 6.75 (m, 1H), 5.01 - 4.94 (m, 2H), 4.75 - 4.68 (m, 2H), 4.36 - 4.17 (m, 6H), 4.04 - 3.95 (m, 1H), 3.72 - 3.64 (m, 2H), 2.80 - 2.76 (m, 3H), 2.25 -2.14 (m, 2H), 2.09 - 1.98 (m, 2H), 1.71 -1.58 (m, 2H) ppm 820 530.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.64 - 9.61 (m, 1H), 9.38 (s, 1H), 8.64 (d, J =8.8 Hz, 1H), 8.53 (d, J = 1.2 Hz, 1H), 8.49 - 8.45 (m, 1H), 8.33 - 8.22 (m, 2H), 7.88 - 7.79 (m, 3H), 7.73 (d, J = 7.6 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.11 - 7.09 (m, 1H), 4.(s, 2H), 4.81 (d, J = 5.6 Hz, 2H), 4.30 - 4.15 (m, 2H), 3.93 (d, J = 6.8 Hz, 2H), 3.75 - 3.61 (m, 2H), 1.30 - 1.20 (m, 1H), 0.64 - 0.55 (m, 2H), 0.37 - 0.34 (m, 2H) ppm 821 560.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.55- 9.52 (m, 1H), 9.05 (s, 1H), 8.64 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.28 - 8.20 (m, 2H), 8.13 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.41 (s, 1H), 7.29 (s, 1H), 4.97 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.45 (s, 2H), 4.25 - 4.19 (m, 2H), 4.03 - 4.00 (m, 2H), 3.72 - 3.63 (m, 2H), 3.(s, 3H), 2.82 - 2.79 (m, 2H), 1.97 - 1.90 (m, 2H) ppm 822 558.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 (brt, J = 5.9 Hz, 1H), 9.23 (s, 1H), 8.52 (d, J = 1.5 Hz, 1H). 8.24 (dd, J = 1.5, 7.8 Hz,1H), 8.07 (d, J = 9.0 Hz, 1H), 7.97 - 7.81 (m, 3H), 7.72 (d, J = 7.8 Hz, 1H), 7.66 (s,1H), 4.97 (s, 2H), 4.74 (brd, J = 5.9 Hz,2H), 4.39 - 4.31 (m, 2H), 4.24 - 4.19 (m, 2H), 4.08 - 3.99 (m, 2H), 3.69 - 3.62 (m,2H), 1.91-1.83 (m, 1H), 0.83 - 0.74 (m, 2H),0.74 - 0.66 (m, 2H) 823 580.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59 -9.56 (m, 1H), 9.10 (s, 1H), 8.53 (d, J = 1.Hz, 1H), 8.44 (br s, 1H), 8.30 -8.18 (m, 2H), 7.90 (d, J = 9.2 Hz, 1H), 7.79 - 7.(m, 2H), 7.50 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 5.95 - 5.60 (m, 1H), 4.98 (s, 2H), 4.94 - 4.69 (m, 4H), 4.29 - 4.19 (m, 2H), 4.14 - 4.10 (m, 2H), 3.70 - 3.64 (m, 2H), 2.85 -2.83 (m, 2H), 1.97 (br t, J =6.0 Hz, 2H) ppm 305 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 824 505.2 1H NMR (40Q MHz, DMSO-d6) 6 = 9.62-9.61 (m, 1H), 9.31 (s, 1H), 8.69 (d, J =8.8 Hz, 1H), 8.56 - 8.47 (m, 2H), 8.38 (d, J = 7.6 Hz, 1H), 8.27 - 8.25 (m, 1H), 7.80 -7.65 (m, 2H), 6.40 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.79 (d, J = 5.6 Hz, 2H), 4.27 -4.15 (m, 2H), 3.72 - 3.64 (m, 2H), 3.56 (s, 3H), 2.47 (s, 3H) ppm 825 564.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.54-9.50 (m, 1H), 9.12 (s, 1H), 8.50 (d, J = 1.Hz, 1H), 8.48 - 8.45 (m, 1H), 8.35 (d, J = 9.2 Hz, 1H), 8.22-8.18 (m, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.40 (s, 1H), 7.29 -7.27 (m, 1H), 4.96 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.28 - 4.16 (m, 2H), 4.05 (br d, J = 3.6 Hz, 2H), 3.(s, 3H), 3.73 - 3.60 (m, 2H), 2.69 - 2.61 (m, 2H), 1.91-1.81 (m, 2H) ppm 826 491.2 1H NMR (400 MHz, METHANOL-d4) 6 = 9.31 (s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.- 8.48 (m, 2H), 8.38 - 8.37 (m, 1H), 8.22 - 8.20 (m, 1H), 7.92 (s, 1H), 7.88 - 7.87 (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), 6.58 -6.55 (m, 1H), 5.05 (s, 2H), 4.92 (s, 2H), 4.37 - 4.31 (m, 2H), 3.69 (s, 3H), 3.55 - 3.51 (m, 2H) ppm 827 576.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.58- 9.55 (m, 1H), 9.12 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.34 - 8.22 (m, 3H), 8.13 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 4.98 (s, 2H), 4.74 (d, J = 5.6 Hz, 2H), 4.46 - 4.33 (m, 4H), 4.28 -4.18 (m, 2H), 3.76 - 3.58 (m, 2H), 1.96 - 1.90 (m, 1H), 1.00 - 0.93 (m, 2H), 0.82 - 0.77 (m, 2H) ppm 828 608.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59-9.58 (m, 1H), 9.14 (s, 1H), 8.52 (d, J = 1.Hz, 1H), 8.46 - 8.21 (m, 4H), 7.73 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.28 (d, J = 7.Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.74 (brd, J = 6.0 Hz, 2H), 4.33 (br d, J = 3.2 Hz, 4H), 4.26 - 4.18 (m, 2H), 3.72 - 3.65 (m, 2H), 3.46 - 3.44 (m, 1H), 2.97 - 2.74 (m, 4H) ppm 829 574.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.55- 9.52 (m, 1H), 8.98 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.29 - 8.20 (m, 2H), 8.10 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.41 (s, 1H), 7.18 (s, 1H), 7.05 -6.89 (m, 2H), 4.97 (s, 2H), 4.71 (d, J = 6.0 Hz, 2H), 4.33 - 4.30 (m, 2H), 4.25 - 4.19 (m, 2H), 3.69 - 3.64 (m, 2H), 3.62 - 3.59 (m, 2H), 3.18 (s, 3H), 2.04- 1.86 (m, 1H), 1.11 -1.02 (m, 2H), 0.86- 0.77 (m, 2H) ppm 830 577.1 1H NMR (400 MHz, METHANOL-d4) 6 = 9.09 - 8.98 (m, 1H), 8.63 - 8.57 (m, 1H), 8.47 - 8.37 (m, 1H), 8.26 - 8.14 (m, 2H), 7.95 - 7.88 (m, 1H), 7.66 - 7.59 (m, 2H),7.19 - 7.12 (m, 1H), 5.06 - 5.02 (m, 4H), 4.35 - 4.32 (m, 2H), 4.08 - 4.02 (m, 2H),3.54 - 3.50 (m, 2H), 2.85 - 2.82 (m, 6H), 2.79 - 2.75 (m, 2H), 2.07 - 1.97 (m, 2H)ppm 831 572.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.59 - 9.58 (m, 1H), 9.10 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.44 (s, 1H), 8.36 - 8.19 (m, 3H), 7.73 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.41 -4.14 (m, 6H), 3.74 - 3.64 (m, 2H), 2.14 - 2.08 (m, 1H), 1.28 - 1.11 (m, 1H), 0.97 - 0.94 (m, 1H), 0.87 - 0.83 (m, 4H) ppm 306 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 832 572.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.60- 9.57 (m, 1H), 9.10 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.42 (s, 1H), 8.35 - 8.19 (m, 3H), 7.73 (d, J = 7.6 Hz, 1H), 7.49 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 4.73 (d, J = 5.6 Hz, 2H), 4.41 - 4.13 (m, 6H), 3.73 - 3.65 (m, 2H), 2.14 - 2.08 (m, 1H), 1.30 - 1.11 (m, 1H), 0.98 - 0.95 (m, 1H), 0.87 - 0.85 (m, 4H) ppm 833 574.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.54-9.53 (m, 1H), 8.97 (s, 1H), 8.51 (d, J = 1.Hz, 1H), 8.40 (brs, 1H), 8.30 (d, J = 2.4 Hz, 1H), 8.24-8.23 (m, 1H), 8.08 (d, J = 9.Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.52-7.50 (m, 1H), 7.41 (s, 1H), 7.33 (d, J = 8.Hz, 1H), 6.96 (d, J = 9.4 Hz, 1H), 4.97 (s, 2H), 4.70 (brd, J = 5.8 Hz, 2H), 4.31 (br t, J = 6.0 Hz, 2H), 4.26 - 4.19 (m, 2H), 3.70 - 3.65 (m, 2H), 3.60 (t, J = 6.0 Hz, 2H), 3.18 (s, 3H), 2.05 -1.91 (m, 1H), 1.08 - 0.96 (m, 2H), 0.83 - 0.71 (m, 2H) ppm 834 573.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.57 - 9.52 (m, 1H), 9.03 - 8.97 (m, 1H), 8.51 (s, 1H), 8.27 - 8.19 (m, 3H), 7.75 - 7.69 (m, 1H), 7.50 - 7.43 (m, 1H), 7.38 - 7.34 (m, 1H), 5.90 (s, 1H), 4.97 (s, 2H), 4.69 (brd, J = 5.6 Hz, 2H), 4.31 - 4.27 (m, 2H), 4.- 4.20 (m, 4H), 3.92 - 3.85 (m, 4H), 3.72 - 3.64 (m, 2H), 2.32 - 2.25 (m, 2H) ppm 835 610.2 1H NMR (400 MHz, DMSO-d6) 0 = 9.63 - 9.54 (m, 1H), 9.14 - 9.07 (m, 1H), 8.56 - 8.48 (m, 1H), 8.43 - 8.37 (m, 1H), 8.27 - 8.21 (m, 2H), 8.08 - 8.00 (m, 1H), 7.77 - 7.70 (m, 2H), 7.51 (s, 1H), 7.12-6.75 (m, 1H), 5.01 -4.94 (m, 2H), 4.78-4.70 (m, 2H), 4.54 (s, 2H), 4.24 - 4.20 (m, 2H), 4.20 - 4.15 (m, 2H), 3.70 - 3.66 (m, 2H), 3.(br s, 3H), 2.91 - 2.87 (m, 2H), 2.02 - 1.95 (m, 2H) ppm 836 559.3 1H NMR (400 MHz, METHANOL-d4) 5 = 9.03 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.(d, J = 3.2 Hz, 1H), 8.26 - 8.18 (m, 2H), 7.88 (d, J = 5.6 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.52 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 6.0 Hz, 1H), 5.04 (s, 2H), 4.95 (d, J = 3.Hz, 2H), 4.34 - 4.32 (m, 2H), 4.06 - 4.03 (m, 2H), 3.55 - 3.50 (m, 2H), 2.90 (s, 6H), 2.79 - 2.73 (m, 2H), 2.03 - 1.98 (m, 2H) ppm 837 559.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.58 - 9.57 (m, 1H), 9.02 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 5.6 Hz, 1H). 7.76 - 7.73 (m, 2H), 7.46 (s, 1H), 6.70 (d, J = 5.6 Hz, 1H), 4.98 (s, 2H), 4.72 (brd, J = 5.6 Hz, 2H), 4.26 - 4.20 (m, 2H), 4.05 - 4.02 (m, 2H), 3.70 - 3.(m, 2H), 2.78 (s, 6H), 2.67 (br d, J = 2.0 Hz, 2H), 1.93 - 1.77 (m, 2H) ppm 838 582.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.60-9.55 (m, 1H), 9.14 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.25 (d, J = 9.4 Hz, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.06 - 5.52 (m, 1H), 5.01 - 4.96 (m, 2H), 4.95 - 4.77 (m, 2H), 4.75 (br d, J = 5.9 Hz, 2H), 4.41 - 4.29 (m, 4H), 4.25 - 4.18 (m, 2H), 3.70 - 3.66 (m, 2H) ppm 307 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 839 575.1 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 (d, J = 5.6 Hz, 1H), 9.20 (s, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 8.36 (m, 2H), 8.23 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.56 (s, 1H), 7.08 (d, J =6.1 Hz, 1H), 4.97 (s, 2H), 4.75 (d, J = 5.8 Hz, 2H), 4.43 (d, J = 6.1 Hz, 2H), 4.26 - 4.19 (m, 2H), 3.70 - 3.59 (m, 4H), 3.17 (s, 3H), 2.10 - 2.04 (m, 1H), 1.01 -0.92 (m, 4H) ppm 840 574.3 1H NMR (400 MHz, METHANOL-d4) 6 = 8.90 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.- 8.19 (m, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.69 - 7.68 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 9.Hz, 1H), 5.04 (s, 2H), 4.82 (s, 2H), 4.40 - 4.38 (m, 2H), 4.37 - 4.32 (m, 2H), 3.72 - 3.70 (m, 2H), 3.56 - 3.50 (m, 2H), 3.28 (s, 3H), 2.12 -1.99 (m, 1H), 1.00 - 0.92 (m, 4H) ppm 841 545.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.59-9.58 (m, 1H), 9.16 (s, 1H), 8.52 (d, J = 1.Hz, 1H), 8.35 - 8.19 (m, 2H), 8.08 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.(s, 1H), 4.97 (s, 2H), 4.75 (d, J = 5.7 Hz, 2H), 4.29 - 4.16 (m, 2H), 4.14 - 4.03 (m, 2H), 3.73 - 3.63 (m, 2H), 2.71 (brt, J = 6.5 Hz, 2H), 2.34 (d, J = 16.0 Hz, 6H), 2.05 - 1.92 (m, 2H) ppm 842 534.3 1H NMR (400 MHz, DMSO-d6) 0 = 9.63 - 9.53 (m, 1H), 9.09 (s, 1H), 8.53 (d, J =1.8 Hz, 1H), 8.43 (s, 1H), 8.28 - 8.17 (m, 3H), 7.91 (d, J = 9.2 Hz, 1H), 7.76 - 7.(m, 1H), 7.68 (d, J = 6.6 Hz, 1H), 7.51 (s, 1H), 7.12 (dd, J = 4.8, 7.4 Hz, 1H), 5.55- 5.28 (m, 1H), 4.98 (s, 2H), 4.87 - 4.77 (m, 1H), 4.74 (d, J = 5.7 Hz, 2H), 4.30 - 4.(m, 2H), 4.03- 3.85 (m, 1H), 3.75 - 3.61 (m, 2H), 3.44 - 3.41 (m, 1H), 3.13 (brdd, J = 2.4, 3.5 Hz, 1H) ppm 843 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.56 (s, 1H), 9.05 (s, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.24 - 8.22 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 6.93 (d, J = 8.Hz, 1H), 4.97 (s, 2H), 4.70 (d, J = 6.0 Hz, 2H), 4.40 - 4.30 (m, 2H), 4.26 -4.14 (m, 4H), 3.70 - 3.64 (m, 2H), 2.05 - 1.95 (m, 1H), 0.88 - 0.87 (m, 2H), 0.83 - 0.81 (m, 2H) ppm 844 558.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59-9.40 (m, 1H), 9.09 (s, 1H), 8.93 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.24 (m, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.44 (s, 1H), 6.72-6.62 (m, 2H), 4.97 (s, 2H), 4.73 (brd, J= 5.6 Hz, 2H), 4.32 (d, J = 4.6 Hz, 2H), 4.27 - 4.11 (m, 4H), 3.75 - 3.62 (m, 2H),1.94 - 1.83 (m, 1H), 0.98 - 0.88 (m, 2H), 0.70 - 0.60 (m, 2H) ppm 845 561.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.56- 9.53 (m, 1H), 8.98 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.41 - 8.34 (m, 1H), 8.26-8.18 (m, 2H), 7.73-7.68 (m, 2H), 7.42 - 7.29 (m, 2H), 6.28 (d, J = 8.8 Hz, 1H), 4.97 (s, 2H), 4.69 (d, J = 6.0 Hz, 2H), 4.34 - 4.28 (m, 2H), 4.24 - 4.21 (m, 2H), 4.19 - 4.16 (m, 2H), 3.71 - 3.66 (m, 2H), 2.98 (s, 6H) ppm 308 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 846 568.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.59- 9.56 (m, 1H), 9.13 (s, 1H), 8.5Q (d, J = 1.6 Hz, 1H), 8.41 (brs, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.27-8.17 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.47 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.95 - 6.67 (m, 1H), 4.97 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.52 - 4.44 (m, 2H), 4.23 - 4.(m, 4H), 3.70 - 3.63 (m, 2H) ppm 847 608.4 1H NMR (400 MHz, DMSO-d6) 5 = 9.59 (m, 1H), 9.11 (s, 1H), 8.53 (s, 1H), 8.30 (s, 2H), 8.25-8.23 (m, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.31 (d, J = 1.8 Hz, 1H), 6.06 - 5.66 (m, 1H), 4.97 (s, 2H), 4.74 (brd, J = 5.Hz, 2H), 4.34 (br s, 4H), 4.26 -4.17 (m, 2H), 3.74 - 3.64 (m, 2H), 1.18 - 1.09 (m, 2H), 1.02 (brs, 2H) ppm 848 531.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.66 - 9.56 (m, 1H), 9.18 (s, 1H), 8.56 - 8.49 (m, 1H), 8.44 - 8.41 (m, 2H), 8.34 - 8.30 (m, 1H), 8.27 - 8.22 (m, 1H), 8.06 - 8.00 (m, 1H), 7.76 - 7.70 (m, 1H), 7.56 (s, 1H), 5.02 - 4.94 (m, 2H), 4.75 (brd, J = 5.6 Hz, 2H), 4.28 - 4.18 (m, 2H), 4.15 - 4.08 (m, 2H), 3.71 - 3.66 (m, 2H), 2.77 (brt, J = 6.Hz, 2H), 2.37 (s, 3H), 2.07 - 1.97 (m, 2H) ppm 849 527.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.68 - 9.65 (m, 1H), 9.43 (s, 1H), 8.75 - 8.60 (m, 4H), 8.54 (s, 1H), 8.35 (s, 1H), 8.26 (d, J =7.6 Hz, 1H), 7.90 - 7.82 (m, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.68 - 7.25 (m, 1H), 4.98 (s, 2H), 4.83 (d, J = 5.6 Hz, 2H), 4.30 - 4.17 (m, 2H), 3.75 - 3.66 (m, 2H) ppm 850 491.2 1H NMR (400 MHz, DMSO-d6) 6 = 9.65 (d, J = 5.8 Hz, 1H), 9.38 (s, 1H), 8.67 - 8.62 (m, 1H), 8.62 - 8.56 (m, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.27 (m, 1H), 7.81 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.58 (m, 1H), 4.98 (s, 2H), 4.(brd, J = 5.6 Hz, 2H), 4.28 - 4.18 (m, 2H), 3.93 (s, 3H), 3.74 - 3.64 (m, 2H) ppm 851 517.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.63-9.60 (m, 1H), 9.38 (s, 1H), 8.68 - 8.63 (m, 1H), 8.62 - 8.57 (m, 2H), 8.54 (d, J = 2.0 Hz, 2H), 8.27 (brd, J = 7.8 Hz, 1H), 7.(s, 1H), 7.77 - 7.66 (m, 2H), 4.98 (s, 2H), 4.82 (brd, J = 5.6 Hz, 2H), 4.29 - 4.16 (m, 2H), 4.08 (id, J = 2.9, 5.9 Hz, 1H), 3.73 - 3.60 (m, 2H), 0.92 - 0.84 (m, 2H), 0.79 - 0.69 (m, 2H) ppm 852 572.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.75 - 9.72 (m, 1H), 9.42 (s, 1H), 8.62 (d, J = 9.2 Hz, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.28- 8.25 (m, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.31 (s, 1H), 4.98 (s, 2H), 4.82 (d, J = 5.6 Hz, 2H), 4.25 - 4.20 (m, 2H), 4.09 - 4.04 (m, 3H), 3.69 - 3.65 (m, 2H), 2.85 - 2.75 (m, 2H), 2.03 - 2.00 (m, 2H), 0.74 - 0.68 (m, 2H), 0.66 - 0.65 (m, 2H) ppm 853 576.3 1H NMR (400 MHz, DMSO-d6) 6 = 9.57 (m, 1H), 9.16 (s, 1H), 8.50 (s, 1H), 8.46 (br s, 1H), 8.42 (d, J= 9.0 Hz, 1H), 8.23 (m, 1H), 8.01 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.29 (m, 1H), 4.97 (s, 2H), 4.73 (m, 2H), 4.29 - 4.21 (m, 6H), 3.69 - 3.65 (m, 2H), 2.17 (m, 1H), 0.97 - 0.87 (m, 4H) ppm 309 WO 2022/103899 PCT/US2021/058865 # LCMS (ESi/M+H) 1H NMR 854 582.3 1H NMR (40Q MHz, DMSO-d6) 6 = 9.59 (t, J = 5.9 Hz, 1H), 9.14 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.41 - 8.32 (m, 1H), 8.29 - 8.20 (rn, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 5.99 - 5.61 (m, 1H), 5.04 - 4.96 (m, 2H), 4.95 - 4.67 (m, 4H), 4.47 - 4.28 (m, 4H), 4.23 (br dd, J = 4.1, 5.7 Hz, 2H), 3.72 - 3.63 (m, 2H) ppm 855 527.9 1H NMR (400 MHz, DMSO-d6) 5 = 9.58 (m, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 8.36 (br s, 1H), 8.26 (m, 1H), 8.15 - 8.08 (m, 2H), 7.85 (m, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 9.4 Hz, 1H), 7.48 (s,1H), 7.11 (m, 1H), 5.20 (m, 1H), 4.98 (s, 2H), 4.(d, J = 6.4 Hz, 2H), 4.26 - 4.19 (m, 2H), 3.71 - 3.66 (m, 2H), 3.19 (d, J = 11.6 Hz, 1H), 2.18-2.11 (m, 1H), 2.11 -2.03 (m, 1H), 1.01 (m, 1H), 0.80 (m, 1H) ppm 856 582.3 1H NMR (400 MHz, DMSO-d6) 5 = 9.59 (m, 1H), 9.14 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.40 (s,1H), 8.37 - 8.33 (m, 1H), 8.31 - 8.22 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.21 (d,J = 8.2 Hz, 1H), 5.94 - 5.65 (m, 1H), 4.98 (s, 2H), 4.92 - 4.72 (m, 4H), 4.38 (s, 4H), 4.25 - 4.21 (m, 2H), 3.70 - 3.66 (m, 2H) ppm Example 5. Assay for ATPase catalytic activity of BRM and BRG-1 The ATPase catalytic activity of BRM or BRG-1 was measured by an in vitro biochemical assay using ADP-GloTM (Promega, V9102). The ADP-Glo™ kinase assay is performed in two steps once the reaction is complete. The first step is to deplete any unconsumed ATP in the reaction. The second step is to convert the reaction product ADP to ATP, which will be utilized by the luciferase to generate luminesce and be detected by a luminescence reader, such as Envision.The assay reaction mixture (10 pL) contains 30 nM of BRM or BRG-1,20 nM salmon sperm DNA (from invitrogen, UltraPure™ Salmon Sperm DNA Solution, cat# 15632011), and 400 pM of ATP in the ATPase assay buffer, which comprises of 20 mM Tris, pH 8, 20 mM MgCI2, 50 mM NaCI, 0.1% Tween- 20, and 1 mM fresh DTT (Pierce™ DTT (Dithiothreitol), cat# 20290). The reaction is initiated by the addition of the 2.5 pL ATPase solution to 2.5 pL ATP/DNA solution on low volume white Proxiplate-3plus plate (PerkinElmer.cat # 6008280) and incubates at room temperature for 1 hour. Then, following addition of 5 pL of ADP-Glo™ Reagent provided in the kit, the reaction incubates at room temperature for minutes. Then, 10 pL of Kinase Detection Reagent provided in the kit is added to convert ADP to ATP, and the reaction incubates at room temperature for 60 minutes. Finally, luminescence measurement is collected with a plate-reading luminometer, such as Envision.BRM and BRG-1 were synthesized from high five insect cell lines with a purity of greater than 90%. IC50 data from the ATPase catalytic activity assay described herein are shown in Tables 5A and 5B below. 310 WO 2022/103899 PCT/US2021/058865 Table 5A. BRM and BRG-1 inhibition Data for Compounds of the invention cpd # BRM iCgo (uM)BRG1IC50 (pM) Ratio* cpd # BRM ICso (uM) BRG1 ICs0 (uM) Ratio* 0.0090 0.0345 3.83 173 0.1080 1.4875 13.780.0075 0.0511 6.80 174 0.0288 0.2657 9.240.0086 0.0850 9.89 175 0.0040 0.0207 5.170.0089 0.0884 9.95 176 0.4370 1.7905 4.100.0181 0.1936 10.70 177 0.0158 0.2223 14.020.0173 0.1272 7.37 178 0.1799 1.3897 7.720.0198 0.1848 9.33 179 0.0333 0.3827 11.490.0905 0.6944 7.67 180 0.0176 0.2717 15.480.0051 0.0198 3.87 181 0.0405 0.3673 9.060.0093 0.0459 4.92 182 0.0445 0.4217 9.470.0745 0.4566 6.12 183 0.0089 0.1014 11.330.2942 1.8418 6.26 184 0.0805 0.7688 9.550.0248 0.4553 18.33 185 0.3566 1.3359 3.750.1465 1.5178 10.36 186 0.0221 0.2539 11.500.0349 0.2000 5.74 187 0.1093 2.6676 24.400.0760 0.7165 9.43 188 0.2871 5.0000 17.420.0117 0.1165 9.98 189 0.1352 0.7511 5.560.0095 0.0447 4.70 190 0.0459 0.3935 8.570.0253 0.2392 9.45 191 0.0601 1.1849 19.730.0136 0.2401 17.62 192 0.0051 0.0327 6.450.0080 0.1181 14.73 193 0.0354 0.2615 7.380.0969 0.5459 5.63 194 0.2193 2.7836 12.690.0730 0.7798 10.68 195 0.0037 0.0313 8.490.7885 5.0000 6.34 196 0.2358 0.7218 3.060.9565 5.0000 5.23 197 0.0193 0.2443 12.640.0189 0.2467 13.08 198 0.2225 0.9667 4.340.0214 0.6332 29.53 199 0.2521 2.4103 9.560.0175 0.3399 19.39 200 0.0081 0.0591 7.310.0162 0.0997 6.14 201 0.0194 0.1768 9.110.2106 1.6384 7.78 202 0.0179 0.1357 7.590.0894 0.5855 6.55 203 0.1540 1.5757 10.230.4330 4.9257 11.38 204 0.0565 0.6789 12.010.2622 2.4747 9.44 205 0.0903 1.4844 16.450.0368 0.4059 11.02 206 0.0080 0.1097 13.710.0239 0.2848 11.93 207 0.4070 5.0000 12.290.2241 1.2277 5.48 208 0.0427 0.3771 8.840.0068 0.0794 11.74 209 0.4979 3.6192 7.270.1223 1.1775 9.63 210 0.0176 0.1742 9.920.0346 0.6806 19.65 211 0.0070 0.0213 3.050.0457 0.6818 14.90 212 0.0143 0.1217 8.510.0775 1.0738 13.85 213 0.0095 0.1319 13.940.0190 0.1978 10.42 214 0.3311 3.3139 10.010.0146 0.1155 7.89 215 0.0070 0.0662 9.470.1761 2.0698 11.75 216 0.0109 0.0937 8.63 311 WO 2022/103899 PCT/US2021/058865 cpd # BRM iCgo (uM) BRG1 IC50 (pM)Ratio* cpd # BRM ICso (uM) BRG1 ICs0 (uM) Ratio* 0.2750 1.7419 6.33 217 0.0612 0.9646 15.770.4271 5.0000 11.71 218 0.1656 1.6219 9.790.0081 0.1347 16.64 219 0.1363 1.2336 9.050.1210 0.5701 4.71 220 0.0160 0.1442 9.020.0157 0.1286 8.19 221 0.0823 0.7942 9.650.0225 0.3244 14.43 222 0.0129 0.1360 10.580.6887 4.9159 7.14 223 0.0069 0.0496 7.160.0342 0.5347 15.63 224 0.0259 0.3655 14.090.0308 0.6479 21.02 225 0.0046 0.0287 6.290.1660 2.1405 12.89 226 0.0111 0.1365 12.290.0048 0.0170 3.52 227 0.0504 0.4608 9.150.0077 0.1030 13.36 228 0.0205 0.2823 13.770.0096 0.0936 9.74 229 0.1188 1.5210 12.810.0320 0.2883 9.02 230 0.0416 0.3994 9.600.0407 0.6101 15.00 231 0.1303 2.3431 17.980.0497 0.6999 14.09 232 0.0585 0.4097 7.000.0203 0.3245 15.97 233 0.0771 1.0802 14.010.0330 0.2573 7.80 234 0.1878 1.5198 8.090.0787 0.8841 11.24 235 0.1541 1.1274 7.32100 0.0080 0.0941 11.83 236 0.0340 0.4400 12.93101 0.0079 0.0577 7.32 237 0.0227 0.4681 20.63102 0.0187 0.1434 7.68 238 0.2615 5.0000 19.12103 0.2525 2.7681 10.96 239 0.0206 0.4217 20.48104 0.2027 0.9026 4.45 240 0.0065 0.0238 3.66105 0.0699 0.9371 13.41 241 0.0623 1.0740 17.23106 0.0761 0.6667 8.76 242 0.2862 3.1650 11.06107 0.0056 0.0560 9.98 243 0.5280 4.6594 8.82108 0.6725 5.0000 7.43 244 0.0207 0.3375 16.32109 0.0169 0.1274 7.52 245 0.0187 0.1763 9.42110 0.0209 0.4068 19.51 246 0.1481 1.5234 10.29111 0.0060 0.0274 4.58 247 0.3249 2.0014 6.16112 0.0129 0.1763 13.71 248 0.0702 0.5899 8.41113 0.0595 0.5832 9.79 249 0.1012 1.0560 10.44114 0.0708 1.6108 22.76 250 0.1047 0.7508 7.17115 0.0235 0.2364 10.05 251 0.1757 1.7026 9.69116 0.0226 0.2361 10.43 252 0.0753 1.3786 18.31117 0.0446 0.3125 7.01 253 0.0207 0.3985 19.26118 0.0249 0.2516 10.11 254 0.0542 0.5165 9.53119 0.0400 0.2211 5.53 255 0.0364 0.4867 13.37120 0.0447 0.4690 10.48 256 0.0490 0.4258 8.69121 0.0867 0.4974 5.73 257 0.0154 0.1074 6.99122 0.0103 0.0677 6.56 258 0.2213 4.1234 18.63123 0.0232 0.2902 12.51 259 0.4670 5.0000 10.71124 0.0378 0.5405 14.29 260 0.6974 5.0000 7.17125 0.0183 0.2240 12.26 261 0.0165 0.2326 14.10 312 WO 2022/103899 PCT/US2021/058865 cpd # BRM iCgo (uM) BRG1 IC50 (pM)Ratio* cpd # BRM ICso (uM) BRG1 ICs0 (uM) Ratio* 126 0.0335 0.2952 8.80 262 0.4657 2.6236 5.63127 0.8458 4.0512 4.79 263 0.0233 0.3482 14.94128 0.0426 0.4681 10.99 264 0.0235 0.5903 25.10129 0.0479 0.5703 11.91 265 0.1670 2.3986 14.36130 0.0107 0.1043 9.77 266 0.8186 5.0000 6.11131 0.0716 0.5096 7.12 267 0.0352 1.0920 30.99132 0.0125 0.2044 16.30 268 0.0163 0.3426 21.00133 0.0615 0.4866 7.91 269 0.1998 5.0000 25.03134 0.1856 2.4647 13.28 270 0.1266 1.5747 12.44135 0.1119 1.0599 9.48 271 0.0161 0.2045 12.70136 0.0334 0.2387 7.15 272 0.2447 4.2296 17.28137 0.0225 0.3824 16.99 273 0.1192 2.7980 23.47138 0.0108 0.0507 4.70 274 0.0696 0.5889 8.46139 0.4318 2.0748 4.81 275 0.0849 1.3209 15.55140 0.0352 0.2433 6.92 276 0.0818 0.5842 7.14141 0.0130 0.1690 12.97 277 0.6148 5.3589 8.72142 0.2302 2.6598 11.55 278 0.0738 1.9132 25.91143 0.0076 0.1085 14.36 279 0.5289 5.0000 9.45144 0.1466 1.3496 9.21 280 0.2118 2.1737 10.26145 0.0036 0.0571 15.77 281 0.0828 1.6505 19.92146 0.0153 0.1972 12.92 282 0.0042 0.0193 4.64147 0.0156 0.3938 25.22 283 0.1969 3.4800 17.67148 0.4547 3.0912 6.80 284 0.0121 0.1779 14.69149 0.0366 0.8104 22.13 285 0.0193 0.4967 25.69150 0.0338 0.3963 11.71 286 0.3514 4.8887 13.91151 0.0608 0.6693 11.00 287 0.0242 0.5937 24.53152 0.1357 2.1401 15.77 288 0.1966 3.4572 17.58153 0.0463 0.4512 9.74 289 0.0598 0.9579 16.01154 0.1424 2.1276 14.94 290 0.1725 1.2411 7.19155 0.0045 0.0252 5.59 291 0.0103 0.0972 9.47156 0.3659 1.9193 5.25 292 0.6670 5.0000 7.50157 0.0145 0.3195 21.99 293 0.2226 2.4122 10.84158 0.0131 0.2617 20.03 294 0.1562 2.7134 17.37159 0.0367 0.4091 11.15 295 0.3851 5.0000 12.98160 0.0030 0.0136 4.54 296 0.3156 5.0000 15.84161 0.0047 0.0452 9.62 297 0.1404 2.0314 14.47162 0.0384 0.5639 14.67 298 0.2213 2.1913 9.90163 0.0208 0.2639 12.71 299 0.8687 6.3572 7.32164 0.1102 1.4106 12.80 300 0.0647 0.7328 11.32165 0.1155 2.1237 18.39 301 0.8582 8.8778 10.34166 0.0168 0.2063 12.29 302 0.2767 2.3534 8.50167 0.0593 0.8271 13.95 303 0.0123 0.1557 12.63168 0.0940 0.8788 9.35 304 0.0094 0.1357 14.43169 0.0030 0.0099 3.33 305 0.0300 0.2790 9.32170 0.1090 0.6894 6.33 306 0.8547 4.2542 4.98 313 WO 2022/103899 PCT/US2021/058865 Ratio is a numeric value produced by dividing BRG1 ICs0 (pM) by BRM IC50 (pM). cpd # BRM iC50 (pM) BRG1 IC (pM) Ratio* cpd # BRM ( ICso (uM ؛ BRG1 ICs0 (uM) Ratio* 171 0.0524 0.4993 9.52 307 0.2674 1.6907 6.32172 0.0092 0.1055 11.42 308 0.0054 0.0158 2.91 Table SB.BRM and BRG-1 Inhibition Data for Compounds of the Invention cpd # BRM IC50 (uM) BRG1 IC50 (pM) Ratio* cpd # BRM IC50 (pM) BRG1 IC50 (pM) Ratio* 309 0.0139 0.2509 18.06 583 0.1087 1.8929 17.41310 0.0058 0.0724 12.46 584 0.7925 5.0000 6.31311 0.0220 0.2830 12.86 585 0.0401 0.3693 9.22312 0.0245 0.3262 13.30 586 0.0055 0.0819 14.77313 0.1048 0.3868 3.69 587 0.0112 0.0639 5.69314 0.0457 0.4804 10.51 588 0.0289 0.4117 14.25315 0.0184 0.3405 18.47 589 0.0777 1.0786 13.88316 0.0471 0.4946 10.49 590 0.0224 0.1774 7.93317 0.0063 0.0348 5.55 591 0.0220 0.2420 10.98318 0.0094 0.0804 8.53 592 0.0529 1.6780 31.69319 0.0211 0.3287 15.59 593 0.2429 2.1903 9.02320 0.0120 0.2260 18.81 594 0.0372 1.1862 31.92321 0.0160 0.1953 12.19 595 0.4078 3.5038 8.59322 0.0110 0.1205 10.96 596 0.6812 5.0000 7.34323 0.0171 0.2300 13.46 597 0.0413 0.4795 11.61324 0.0248 0.6135 24.73 598 0.0293 0.9907 33.79325 0.0106 0.1737 16.33 599 0.0588 0.7367 12.54326 0.0099 0.0810 8.22 600 0.0132 0.1760 13.32327 0.0192 0.2908 15.15 601 0.2150 1.9096 8.88328 0.8429 5.0000 5.93 602 0.0158 0.1579 9.98329 0.0086 0.1302 15.19 603 0.0107 0.1169 10.88330 0.0110 0.4727 43.09 604 0.0057 0.0569 10.00331 0.0135 0.4179 30.98 605 0.0117 0.1869 16.04332 0.0166 0.2245 13.49 606 0.0075 0.1246 16.72333 0.0171 0.2270 13.29 607 0.0446 0.7023 15.74334 0.0212 0.3772 17.82 608 0.0445 0.9524 21.42335 0.0243 0.2884 11.87 609 0.0392 1.1137 28.40336 0.0066 0.1067 16.08 610 0.0513 1.1099 21.62337 0.0219 0.2115 9.67 611 0.0388 0.7132 18.38338 0.0201 0.2186 10.88 612 0.0266 0.3497 13.16339 0.0096 0.0858 8.89 613 0.2134 2.2212 10.41340 0.0222 0.3093 13.96 614 0.0951 0.8615 9.06341 0.0251 0.1847 7.37 615 0.0221 0.3581 16.22342 0.2835 4.3205 15.24 616 0.0082 0.4424 54.03343 1.3471 5.0000 3.71 617 0.0904 2.5430 28.12344 0.0076 0.0203 2.68 618 0.0090 0.1260 14.00345 0.0150 0.2511 16.77 619 0.0056 0.0627 11.17346 0.3675 2.7742 7.55 620 0.0168 0.1577 9.37 314 WO 2022/103899 PCT/US2021/058865 cpd #BRM IC50 (^M) BRG1 IC50 (pM)Ratio* cpd #BRMIC50 (uM) BRG1 1C50 (uM)Ratio*347 1.2297 3.7312 3.03 621 0.0749 0.4080 5.44348 0.0743 2.5579 34.42 622 0.0274 0.1092 3.98349 0.0241 0.2526 10.47 623 0.0110 0.0236 2.15350 0.0081 0.1054 12.99 624 0.0200 0.0381 1.90351 5.0000 5.0000 1.00 625 0.0367 0.5150 14.05352 0.0602 0.4830 8.02 626 0.0200 0.4614 23.08353 0.0095 0.1247 13.13 627 0.0039 0.0050 1.28354 0.0140 0.4149 29.57 628 0.0027 0.0097 3.60355 0.0087 0.0639 7.36 629 0.0100 0.0850 8.49356 3.3085 5.0000 1.51 630 0.0480 1.1578 24.14357 0.0214 0.2931 13.72 631 1.1941 5.0000 4.19358 0.0046 0.0354 7.69 632 0.0583 1.1295 19.38359 5.0000 5.0000 1.00 633 2.2349 5.0000 2.24360 0.9737 5.0000 5.14 634 0.0073 0.0819 11.28361 0.0074 0.1448 19.62 635 0.1677 2.5286 15.08362 0.0169 0.2379 14.06 636 0.2709 4.2631 15.73363 0.2062 5.0000 24.25 637 0.0200 0.2074 10.34364 0.0190 0.2314 12.21 638 0.2266 0.8829 3.90365 0.0131 0.3248 24.88 639 0.1017 0.7795 7.66366 0.3242 2.9626 9.14 640 0.6151 4.4017 7.16367 0.0084 0.1508 17.87 641 0.0136 0.1574 11.56368 5.0000 5.0000 1.00 642 0.1562 2.9466 18.87369 0.0361 0.4155 11.52 643 0.1082 0.8887 8.21370 Q.0146 0.1522 10.43 644 0.0064 0.1696 26.34371 Q.1965 5.0000 25.45 645 0.0098 0.1705 17.38372 0.0109 0.1173 10.78 646 0.0121 0.2472 20.44373 0.0129 0.1383 10.75 647 0.0559 0.3697 6.61374 0.0088 0.0707 8.04 648 0.0050 0.0194 3.85375 0.0427 0.6296 14.74 649 0.1265 0.7502 5.93376 0.0664 0.5353 8.06 650 0.0127 0.1147 9.04377 0.0124 0.1518 12.27 651 0.0553 1.7007 30.77378 0.0117 0.1619 13.88 652 0.4428 3.1913 7.21379 0.2582 1.7106 6.63 653 0.2303 1.7209 7.47380 0.0982 0.5109 5.20 654 0.1037 2.5701 24.78381 0.0194 0.2409 12.43 655 0.2489 3.9320 15.80382 0.0091 0.1200 13.22 656 0.0122 0.1281 10.50383 0.0066 0.0724 10.88 657 0.0353 0.2019 5.73384 0.0143 0.4073 28.41 658 0.0070 0.3418 48.50659 0.0427 1.0364 24.28386 0.0092 0.1397 15.24 660 0.0072 0.0590 8.17387 0.0683 0.7268 10.65 661 0.0439 0.3011 6.86388 0.0184 0.5874 31.86 662 0.0367 0.1726 4.71389 0.0137 0.5278 38.63 663 0.6730 5.0000 7.43390 0.0607 1.0465 17.24 664 1.7471 5.0000 2.86391 0.0287 0.4560 15.87 665 0.0064 0.0868 13.54 315 WO 2022/103899 PCT/US2021/058865 cpd #BRM IC50 (^M) BRG1 IC50 (pM)Ratio* cpd #BRMIC50 (uM) BRG1 1C50 (uM)Ratio*392 0.0421 1.1020 26.15 666 0.0242 0.2677 11.06393 0.0190 0.6384 33.52 667 0.0390 0.5165 13.24394 0.0058 0.0879 15.21 668 0.0084 0.0734 8.70395 0.0041 0.0586 14.47 669 0.0171 0.3236 18.96396 0.0059 0.1035 17.40 670 0.0101 0.0883 8.79397 0.0152 0.1750 11.51 671 4.0045 5.0000 1.25398 0.1848 0.9191 4.97 672 0.0152 0.2086 13.70399 0.0078 0.1138 14.57 673 0.5679 4.9915 8.79400 0.0204 0.4784 23.51 674 3.7806 5.0000 1.32401 1.3209 5.0000 3.79 675 0.8839 5.0000 5.66402 0.0057 0.0609 10.67 676 0.0030 0.0355 11.70677 0.0038 0.0357 9.28404 0.0084 0.1424 17.03 678 0.0545 0.5487 10.07405 0.0109 0.1884 17.27 679 0.0189 0.4228 22.41406 0.0050 0.0697 13.86 680 0.0327 0.9694 29.69407 0.0125 0.0586 4.69 681 0.0330 0.3147 9.53408 0.4756 2.2706 4.77 682 0.0103 0.1643 15.88409 0.0166 0.1426 8.58 683 0.0763 0.7954 10.42410 0.1650 1.1019 6.68 684 0.4840 5.0000 10.33411 0.0146 0.2752 18.90 685 0.7152 5.0000 6.99412 0.0765 0.6528 8.53 686 0.0143 0.1994 13.91413 0.0129 0.2098 16.27 687 0.0197 0.3603 18.34414 0.0233 0.1927 8.27 688 0.2574 1.7119 6.65415 0.0206 0.4940 23.93 689 0.0402 0.8817 21.94416 0.0983 2.1252 21.63 690 0.0235 1.2862 54.81417 0.2527 5.0000 19.79 691 0.0095 0.1589 16.64418 0.0136 0.1932 14.19 692 0.0060 0.0849 14.09419 0.0245 0.3837 15.63 693420 0.0042 0.0426 10.13 694 0.0342 0.2868 8.38421 0.0568 0.8276 14.57 695 0.0433 0.4204 9.72422 0.0109 0.3102 28.45 696 0.0068 0.1284 18.76423 0.0152 0.4911 32.23 697 0.0049 0.0379 7.66424 0.0208 0.6026 29.03 698 0.1930 4.7234 24.47425 0.1008 0.9657 9.58 699 0.2751 2.2127 8.04426 0.0238 0.1360 5.71 700 0.0145 0.7576 52.11427 0.0473 0.4311 9.12 701 0.0872 0.8685 9.96428 0.0503 0.3241 6.45 702 0.0102 0.9599 93.83429 0.0074 0.0764 10.32 703 0.0368 0.2982 8.10430 0.4769 2.4113 5.06 704 0.0911 2.1107 23.18431 0.0161 0.1516 9.43 705 0.0043 0.Q581 13.63432 1.4960 5.0000 3.34 706 0.0050 0.0469 9.39433 0.3314 4.5044 13.59 707 0.0546 0.2641 4.84434 0.1176 1.5893 13.52 708 0.0529 0.9073 17.15435 0.2302 4.2477 18.45 709 0.0376 0.4355 11.57436 0.0150 0.2259 15.10 710 0.0298 0.1526 5.13 316 WO 2022/103899 PCT/US2021/058865 cpd #BRM IC50 (^M) BRG1 IC50 (pM)Ratio* cpd #BRMIC50 (uM) BRG1 1C50 (uM)Ratio*437 0.0248 0.2921 11.79 711 0.0093 0.2548 27.53438 0.0318 0.3568 11.23 712 0.0086 0.1024 11.90439 0.0044 0.0438 10.04 713 0.0459 0.9865 21.51440 0.0323 0.4532 14.01 714 0.0549 0.6674 12.16441 0.0117 0.0995 8.52 715 0.0054 0.0221 4.12442 0.0164 0.1785 10.89 716 1.7325 4.7719 2.75443 0.0347 1.2679 36.53 717 0.0770 0.4322 5.61444 0.0130 0.0275 2.12 718 0.0105 0.0996 9.44445 0.0204 0.6581 32.29 719 0.0426 0.5801 13.62446 0.0112 0.0317 2.83 720 0.0436 0.2312 5.30447 0.0221 0.2220 10.05 721 0.1879 5.0000 26.60448 0.2628 3.6691 13.96 722 0.0088 0.7163 81.47449 0.0349 0.4910 14.08 723 0.0402 0.6673 16.58450 0.0149 0.1829 12.27 724 0.1222 2.2493 18.41451 0.0050 0.0080 1.60 725 0.0268 0.2937 10.95452 0.0440 0.9577 21.77 726 0.0247 0.2925 11.83453 0.0274 0.5954 21.75 727 0.1033 1.2228 11.84454 0.0252 0.2129 8.46 728 0.0123 0.0296 2.42455 5.0000 5.0000 1.00 729 0.0446 1.9188 42.98456 0.0185 0.3983 21.49 730 0.0164 0.8136 49.65457 0.0059 0.0483 8.14 731 0.0184 0.1984 10.80458 0.0192 0.6539 34.03 732 0.0093 0.0925 9.97459 0.1925 5.0000 25.98 733 0.0094 0.0842 8.96460 0.0242 0.2350 9.71 734 0.0063 0.0862 13.67461 1.5870 5.0000 3.15 735 0.0082 0.1101 13.49462 1.7150 5.0000 2.92 736 1.1376 3.8956 3.42463 0.0078 0.1190 15.21 737 0.0104 0.2270 21.91464 0.0360 0.9860 27.40 738 0.0132 0.4281 32.33465 0.1023 1.5606 15.25 739 0.0127 0.2213 17.37466 0.1219 0.8323 6.83 740 0.0482 1.0808 22.41467 0.0236 0.1020 4.32 741 0.0066 0.0934 14.12468 0.0249 0.1907 7.67 742 0.0240 0.4781 19.92469 2.3433 4.2602 1.82 743 0.0275 0.1196 4.35470 0.0748 0.9542 12.76 744 0.4317 3.9395 9.13471 0.1672 0.8843 5.29 745 0.0045 0.0279 6.27472 0.0250 0.3729 14.93 746 0.0222 0.5671 25.51473 0.0109 0.1470 13.46 747 0.0088 0.1184 13.42474 0.2296 4.6942 20.44 748 0.0121 0.1537 12.75475 0.2154 1.6789 7.79 749 0.0126 0.2095 16.64476 0.0037 0.0366 9.82 750 0.0040 0.0183 4.62477 0.0452 0.2935 6.50 751 0.0362 2.2969 63.48478 0.0255 0.2500 9.80 752 1.0370 3.8127 3.68479 0.0483 0.1893 3.92 753 0.0142 0.2025 14.28480 0.0051 0.0602 11.83 754 0.0191 0.1915 10.04481 0.0132 0.1132 8.58 755 0.0071 0.1244 17.47 317 WO 2022/103899 PCT/US2021/058865 cpd #BRM IC50 (^M) BRG1 IC50 (pM)Ratio* cpd #BRMIC50 (uM) BRG1 1C50 (uM)Ratio*482 0.0231 0.2336 10.09 756 0.0151 0.1761 11.62483 0.0438 1.2250 27.99 757 0.0149 0.2944 19.81484 0.0137 0.2894 21.16 758 0.0356 0.5066 14.23485 0.0130 0.1886 14.45 759 0.0053 0.0533 9.97486 1.1644 5.0000 4.29 760 0.0088 0.0622 7.05487 0.0219 0.3435 15.66 761 0.0087 0.0679 7.77488 0.0127 0.0908 7.17 762 5.0000 5.0000 1.00489 0.0159 0.1812 11.37 763 0.0053 0.0454 8.52490 0.0561 0.7866 14.02 764 0.0095 0.1588 16.66491 0.0058 0.0628 10.83 765 0.0235 0.2844 12.08492 0.0044 0.0191 4.38 766 0.0171 0.1791 10.47493 0.1789 0.9210 5.15 767 0.0174 0.1941 11.17494 0.0224 0.0985 4.39 768 0.0107 0.1257 11.76495 0.0631 0.9812 15.54 769 0.0084 0.0264 3.16496 0.1569 2.3859 15.21 770 0.0164 0.3387 20.67497 0.0259 0.4115 15.92 771 0.0105 0.1718 16.35498 0.0266 0.4395 16.52 772 0.3971 2.8809 7.26499 0.2896 1.1935 4.12 773 0.0385 1.1656 30.25500 0.2078 3.5151 16.91 774 0.0120 0.1737 14.44501 0.0099 0.1352 13.59 775 0.0125 0.1519 12.13502 0.0080 0.1205 14.99 776 0.0063 0.1001 15.77503 0.0058 0.0737 12.62 777 0.0740 0.9814 13.26504 0.0286 0.2131 7.45 778 0.0258 0.4153 16.09505 0.5386 5.0000 9.28 779 0.0055 0.0117 2.13506 0.0492 0.6452 13.12 780 0.0290 0.5153 17.78507 0.3869 2.4281 6.28 781 0.0279 0.7132 25.53508 0.0131 0.1374 10.53 782 0.0087 0.0435 4.99509 0.0064 0.0269 4.21 783 0.0311 0.4443 14.27510 0.0139 0.1417 10.20 784 0.0246 0.2123 8.62511 0.3290 0.8349 2.54 785 0.0858 1.3287 15.49512 0.0287 0.2174 7.58 786 0.0156 0.1583 10.14513 0.0169 0.1640 9.70 787 0.0135 0.1937 14.38514 0.0589 0.4647 7.89 788 0.6197 4.1467 6.69515 0.2314 2.5980 11.23 789 0.0059 0.0303 5.10516 0.0122 0.0850 6.98 790 0.0122 0.0614 5.03517 0.4289 5.0000 11.66 791 0.0197 0.0435 2.21518 4.5614 5.0000 1.10 792 0.0137 0.1352 9.88519 0.0133 0.1443 10.89 793 0.0118 0.1403 11.88520 0.0214 0.2633 12.29 794 0.0066 0.0304 4.60521 0.0597 0.4238 7.10 795 0.1222 4.1141 33.67522 0.0138 0.0621 4.48 796 0.0208 0.2723 13.06523 0.0116 0.1806 15.53 797 0.0188 0.1897 10.11524 0.0146 0.1710 11.68 798 0.0074 0.0438 5.90525 0.0251 0.3731 14.85 799 0.0255 0.6629 26.04526 0.0221 0.2503 11.34 800 0.1686 0.6359 3.77 318 WO 2022/103899 PCT/US2021/058865 cpd #BRM IC50 (^M) BRG1 IC50 (pM)Ratio* cpd #BRMIC50 (uM) BRG1 1C50 (uM)Ratio*527 0.0209 0.1770 8.47 801 0.1110 1.4430 13.00528 0.0079 0.0336 4.24 802 0.0081 0.0671 8.31529 0.1731 0.6713 3.88 803 0.0081 0.1048 12.88530 0.0195 0.2177 11.19 804 0.0158 0.6462 40.93531 0.1767 5.0000 28.30 805 0.0262 0.3025 11.56532 0.0064 0.1197 18.84 806 0.0923 0.8006 8.67533 0.0073 0.0914 12.51 807 0.0191 0.4860 25.47534 0.0061 0.0763 12.41 808 0.0840 1.0502 12.50535 0.6374 5.0000 7.84 809 0.0069 0.2694 39.28536 0.0104 0.5899 56.64 810 0.0083 0.1854 22.29537 0.0099 0.0616 6.24 811 5.0000 5.0000 1.00538 0.1141 1.6741 14.67 812 0.0458 0.6618 14.46539 0.0122 0.1532 12.53 813 0.0381 0.4772 12.52540 0.0307 0.6325 20.63 814 0.0214 0.2223 10.40541 0.1312 5.0000 38.11 815 0.1927 1.4460 7.51542 0.0168 0.2288 13.60 816 0.0423 0.7638 18.04543 0.0202 0.3829 18.97 817 0.0124 0.1431 11.55544 0.0418 1.0209 24.42 818 0.0624 1.6796 26.90545 0.0077 0.0659 8.60 819 0.0064 0.0467 7.26546 1.8162 5.0000 2.75 820 0.0961 1.3756 14.31547 0.2928 5.0000 17.08 821 0.0797 0.9590 12.03548 0.0054 0.0517 9.59 822 0.0367 0.4576 12.47549 0.0073 0.1308 17.80 823 0.0613 1.0931 17.84550 0.0053 0.0639 12.09 824 0.7420 4.8192 6.49551 0.0203 0.3986 19.65 825 0.0319 0.2456 7.70552 0.0098 0.1903 19.48 826 3.1971 5.0000 1.56553 0.0204 0.4576 22.48 827 0.0131 0.1526 11.63554 0.0086 0.0831 9.64 828 0.0451 2.3687 52.48555 0.0046 0.0250 5.44 829 1.6557 5.0000 3.02556 1.6996 5.0000 2.94 830 0.5764 2.7603 4.79557 0.0113 0.2354 20.89 831 0.0352 1.1635 33.09558 0.0093 0.1387 14.96 832 0.0155 0.9056 58.26559 3.9323 5.0000 1.27 833 2.3216 5.0000 2.15560 0.4980 5.0000 10.04 834 0.0202 0.2909 14.40561 0.0672 0.8394 12.50 835 0.0171 0.1561 9.15562 0.4248 5.0000 11.77 836 0.1048 0.6505 6.21563 0.0271 0.4485 16.52 837 0.0330 0.1634 4.95564 0.0336 0.8813 26.25 838 0.0275 1.0648 38.76565 0.0115 0.1383 12.06 839 5.0000 5.0000 1.00566 0.0326 0.6786 20.83 840 3.9984 5.0000 1.25567 0.0328 0.5340 16.28 841 0.2902 2.0763 7.16568 0.1063 1.0575 9.95 842 0.0299 0.3288 10.98569 0.1557 0.5172 3.32 843 0.0562 0.4837 8.61570 0.0669 0.5570 8.32 844 0.0190 0.3795 19.99571 0.3314 2.2781 6.87 845 0.0212 0.1838 8.66 319 WO 2022/103899 PCT/US2021/058865 cpd # BRM IC50 (pM) BRG1 IC50 (pM) Ratto* cpd # BRM IC50 (pM) BRG1 IC50 (pM) Ratio* 572 0.0084 0.1356 16.08 846 0.4062 4.5733 11.26573 0.0079 0.0438 5.56 847 0.0194 0.3762 19.41574 0.2738 1.7766 6.49 848 0.2156 2.1791 10.10575 0.0054 0.0823 15.34 849 0.6060 5.0000 8.25576 0.0889 1.6763 18.86 850 0.6637 4.5607 6.87577 0.5693 2.1548 3.78 851 0.7080 2.5737 3.64578 0.0277 0.5255 19.00 852 0.0098 0.1764 17.95579 0.0084 0.0369 4.40 853 0.0126 0.2050 16.24580 0.1058 1.7642 16.67 854 0.1049 2.0699 19.74581 0.1554 2.3662 15.23 855 0.3953 3.7956 9.60582 1.2358 5.0000 4.05 856 0.0119 0.6638 55.91 Example 6. Synthesis of Compound A BRG1/BRM Inhibitor compound A has the structure: Compound A Compound A was synthesized as shown in Scheme 1 below.Scheme 1. Synthesis of Compound A ABC E G H The ATPase catalytic activity of BRM or BRG-1 in the presence of Compound A was measuredby the in vitro biochemical assay using ADP-Glo™ (Promega, V9102) described above. Compound A was found to have an IC50 of 10.4 nM against BRM and 19.3 nM against BRG1 in the assay.
Example 7. Effects of BRG1/BRM ATPase inhibition on the Growth of Uveal Melanoma and Hematological Cancer Cell Lines Procedure: Uveal melanoma cell lines (92-1, MP41, MP38, MP46), prostate cancer cell lines(LNCAP), lung cancer cell lines (NCI-H1299), and immortalized embryonic kidney lines (HEK293T) were 320 WO 2022/103899 PCT/US2021/058865 plated into 96 well plates with growth media (see Table 6). BRG1/BRM ATPase inhibitor, Compound A, was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Cells were incubated at 37 degrees Celsius for 3 days. After three days of treatment, the media was removed from the cells and 30 microliters of TrypLE (Gibco) was added to cells for minutes. Cells were detached from the plates and resuspended with the addition of 170 microliters of growth media. Cells from two DMSO-treated control wells were counted, and the initial number of cells plated at the start of the experiment, were re-plated into fresh-compound containing plates for an additional four days at 37 degrees Celsius. At day 7, cells were harvested as described above. On day and day 7, relative cell growth was measured by the addition of Cell-titer gio (Promega) and luminescence was measured on an Envision plate reader (Perkin Elmer). The concentration of compound at which each cell line ’s growth was inhibited by 50% (GI50), was calculated using Graphpad Prism, and is plotted below. For multiple myeloma cell lines (OPM2, MM1S, LP1), ALL cell lines (TALL1, JURKAT, RS411), DLBCL cell lines (SUDHL6, SUDHL4, DB, WSUDLCL2, PFEIFFER), AML cell lines (OCIAML5), MDS cell lines (SKM1), ovarian cancer cell lines (OV7, TYKNU), esophageal cancer cell lines (KYSE150), rhabdoid tumor lines (RD, G402, G401, HS729, A204), liver cancer cell lines (HLF, HLE, PLCRPF5), and lung cancer cell lines (SW1573, NCIH2444), the above methods were performed with the following modifications: Cells were plated in 96 well plates, and the next day, BRG1/BRM ATPase inhibitor, Compound A, was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar. At the time of cell splitting on days 3 and 7, cells were split into new well plates, and fresh compound was added four hours after re-plating.Table 6 lists the tested cell lines and growth media used. 321 WO 2022/103899 PCT/US2021/058865 Table 6. Cell Lines and Growth Media Cell Line Source Growth Media 92-1 SIGMA RPMI1640 + 20% FBSA204 ATCC McCoy's SA +10% FBSDB ATCC RPMI1640 +10% FBSG401 ATCC McCoy's SA +1096 FBSG402 ATCC McCoy's SA +10% FBSHEK293T ATCC DMEM + 10% FBSHIE JCRB DMEM + 10% FBSHLF JCRB DMEM + 10% FBSHS729 ATCC DMEM + 10% FBSJURKAT ATCC RPMI1640 + 10% FBSKYSE15O DSMZ RPMI1640/Ham's F12 +10% FBSENCAP ATCC RPMI1640 + 10% FBSLP1 DSMZ IMDM + 20% FBSMM1S ATCC RPMI1640 +10% FBSMP38 ATCC RPMil.640 + 20% FBSMP41 ATCC RPMil.640 + 20% FBSMP46 ATCC RPMil64O + 2O% FBSNCl H1299 ATCC RPMI1640 + 10% FBSNCIH2444 ATCC RPMI1640 + 20% FBSOCIAML5 DSMZ alpha-MEM + 20% FBS +10ng/ml GM-CSFOP M2 DSMZ RPMI1640 + 10% FBSOV7 ECACC DMEM/Ham's F12 (1:1) + 2mM Glutamine +10% FBS +0.5 ug/ml hydrocortisone +■ lOug/ml insulinPFEIFFER ATCC RPMI1640 + 10% FBSPLCPRF5 ATCC EMEM +10% FBSRD ATCC DMEM + 10% FBSRS411 ATCC RPMI1640 +10% FBSSKM1 JCRB RPMi 1.640 + 1.0% FBSSUDHL4 DSMZ RPMi 1.640 + 1.0% FBSSUDHL6 ATCC RPMI164O + 2O% FBSSW1573 ATCC DMEM + 10% FBSTALL1 JCRB RPMI1640 + 10% FBSTYKNU JCRB EMEM +20% FBSWSUDLCL2 DSMZ RPMI1640 + 10% FBSResults: As shown in FIG. 1, the uveal melanoma and hematologic cancer cell lines were moresensitive to BRG1/BRM inhibition than the other tested cell lines. Inhibition of the uveal melanoma and hematologic cancer cell lines was maintained through day 7.
Example 8. Comparison of BRG1/BRM Inhibitors to clinical PKC and MEK inhibitors in uveal melanoma cell lines Procedure: Uveal melanoma cell lines, 92-1 or MP41, were plated in 96 well plates in thepresence of growth media (see Table 5). BAF ATPase inhibitors (Compound A), PKC inhibitor (LXS196; MedChemExpress), or MEK inhibitor (Selumetinib; Selleck Chemicals) were dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Ceils were incubated at 37 degrees Celsius for 3 days. After three days of treatment, cell growth was measured with Cell-titer glow (Promega), and luminescence was read on an Envision plate reader (Perkin Elmer).Results: As shown in FIG. 2A and FIG. 2B, Compound A showed comparable growth inhibition ofuveal melanoma cells as the clinical PKC and MEK inhibitors. Further, compound A was found to result in a faster onset of inhibition than the clinical PKC and MEK inhibitors. 322 WO 2022/103899 PCT/US2021/058865 Example 9. Synthesis of Compound B BRG1/BRM Inhibitor Compound B has the structure: Compound B Compound B was synthesized as shown in Scheme 2 below.Scheme 2. Synthesis of Compound B Compound B Preparation of (S)-1 -(methyisuifonyi)-N-(4-(methybhio)-1 -oxo-1 -((4-(3-(pyridm-4- yi)phenyi)thiazol-2-yl)amino)butan-2-yi)-1 H-pyrrote-3-carboxamide (Compound B) To a mixture of (2S)-2-amino-4-methylsulfanyl-N-[4-[3-(4-pyridy5)pheny5]thiazol-2-yl]butanamide (2 g, 4.75 mmol, HCI salt) and 1-methylsulfonylpyrrole-3-carboxyhc acid (898.81 mg, 4.75 mmol) in DMF (20 mL) was added EDCi (1.37 g, 7.13 mmol), HOBt (962.92 mg, 7.13 mmol), and DIEA (2.46 g, 19.0Q mmol, 3.31 mL) and the mixture was stirred at 25 °C for 3 hours. The mixture was poured into H2O (1mL) and the precipitate was collected by filtration. The solid was triturated in MeOH (20 mL) and the precipitate was collected by filtration. The solid was dissolved in DMSO (10 mL) and then the mixture was poured into MeOH (50 mL) and the formed precipitate was collected by filtration and lyophilized to give Compound B (2.05 g, 3.66 mmol, 77.01% yield) as a white solid. LCMS (ESI) m/z [M+Hp=555.9. 1H NMR (400 MHz, DMSO) 6 12.49 (s, 1H), 8.68-8.66 (m, 2H), 8.46 (d, J=7.2 Hz, 1H), 8.31-8.30 (m, 1H), 8.02-8.00 (m, 1H), 7.94-7.96 (m, 1H), 7.83 (s, 1H), 7.73-7.74 (m, 3H), 7.61-7.57 (m, 1H), 7.31-7.29 (m, 1H), 6.79-6.77 (m, 1H), 4.74-4.69 (m, 1H), 3.57 (s, 3H), 2.67-2.53 (m, 2H), 2.13-2.01 (m, 5H). SFC: AS- 3-MeOH (DEA)-40-3mL-35T.lcm, t = 0.932 min, ee%=100%.
Example 10. Effects of BRG1/BRM ATPase inhibition on the growth of uveal melanoma, hematological cancer, prostate cancer, breast cancer, and Ewing’s sarcoma celllines Procedure: All cell lines described above in Example 7 were also tested as described above with Compound B. In addition, the following cell lines were also tested as follows. Briefly, for Ewing ’s sarcoma cell lines (CADOES1, RDES, SKES1), retinoblastoma cell lines (WERIRB1), ALL cell lines (REH), AML cell lines (KASUMH), prostate cancer cell lines (PC3, DU145 22RV1), melanoma cell lines (SH4, SKMEL28, WM115, COLO829, SKMEL3, A375), breast cancer cell lines (MDAMB41 5, CAMA1, 323 WO 2022/103899 PCT/US2021/058865 MCF7, BT474, HCC1419, DU4475, BT549), B-ALL cell lines (SUPB15), CML cell lines (K562, MEG01), Burkitt's lymphoma cell lines (RAMOS2G64C10, DAUDI), mantle cell lymphoma cell lines (JEKO1, REC1), bladder cancer cell lines (HT1197), and lung cancer cell lines (SBC5), the above methods were performed with the following modifications: Cells were plated in 96 well plates, and the next, day, BRG1/BRM ATPase inhibitor, Compound B, was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar. At the time of cell splitting on days 3 and 7, cells were split into new 96 well plates, and fresh compound was added four hours after re-plating.Table 7 lists the tested cell lines and growth media used.Table 7.Cell Lines And Growth Media Results: As shown in FIG. 3, the uveal melanoma, hematologic cancer, prostate cancer, breast Cell Line !Source Growth Media 22RV1 ATCC RPMI1540+ 10% FBSA.375 [ATCC DMEM 4■ :10% FBSBT474 ATCG Hybricare medium •1.5 ؛ g/L sodium bicarbonate + 104؟ FBSBT549 ATCC RPMI1640 + 0.023 iU/mi insuHn + 10% FBSCADOES1 [DSMZ RPMI1640+ 10% FBSCAMA1 I ATCC EMEM + 10% FBSCOLO829 IATCC R PM 11640 + 3.0% FBSDAU DiIATCCRPMI1540+ 10% FBSDU145 ATCC EMEM + 10% FBSDU4475 IATCC R PM 11540+ 10% FBSHCC1419 IATCC RPM 11540+ 10% FBSHT1197 IATCC EMEM + 10% FBSIEKO1[ATCCRPMI164020% FBSK562IATCCIM DM + 10% FBSKASUMll| ATCCRPMI1640 + 10% FBSMCF7 ‘ATCC EMiEM +0.01 mg/ml bovine insu ؛؛n+ 10% FBSMDAMB415 ATCC Leibovitz's L-15 + 2mM L-giutamine + 10 mcg/rnl insulin + 10 mcg/m! gjutathione + 15% FBSMEGO! IATCC RPMI1540+ 10% FBSPC 3 l.ATCC F-12K+ 10% FBSRAMOS2G64C10 l.ATCC RPM 11540+ 10% FBSRDES IATCC RPM 11540+ 15% FBSRECI IATCC RPMI1540+ 10% FBSREH IATCC RPMI164010% FBSSBC5ijCRBFBS ؟/ 10 + EMEMSHA IATCC DMEM + 10% FBSSKES1 ATCC McCoy's 5A + 15% FBSSKMEL28 I ATCC EMEM + 10% FBS5KMEL3 IATCC McCoy's 5A+ 15% FBSSUP815 IATCC IMDM -4 ■؛ mM L-glutamine 4• 1.5 g/L sodium bicarbonate + 0.05 rnM 2-mercaptcethancl + 20% FBSWERiRBl l.ATCC RPMI1540+ 10% FBSWM115 IATCC EMEM + 10% FBS cancer, and Ewing ’s sarcoma cell lines were more sensitive to BRG1/BRM inhibition than the other tested cell lines. Inhibition of the uveal melanoma, hematologic cancer, prostate cancer, breast cancer, and Ewing ’s sarcoma cell lines was maintained through day 7.
Example 11. Effects of BRG1/BRM ATPase inhibition on the growth of cancer ceil lines. Procedure:A pooled cell viability assay was performed using PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) as previously described ("High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines ", Yu et al, Nature Biotechnology 34, 419-423, 2016), with the following modifications. Cell lines were obtained from the Cancer Cell Line Encyclopedia (CCLE) collection and adapted to RPMI-1640 medium without phenol red, supplemented with 10% heat-inactivated fetal bovine serum (FBS), in order to apply a unique infection and pooling protocol to such a big compendium of cell lines. A lentiviral spin-infection protocol was executed to introduce a 24 nucleotide-barcode in each cell line, with an estimated multiplicity of infection (MOI) of 1 for all cell lines, using blasticidin as selection marker. Over 750 PRISM cancer cell lines stably 324 WO 2022/103899 PCT/US2021/058865 barcoded were then pooled together according to doubling time in pools ot 25. For the screen execution, instead of plating a pool of 25 cell lines in each well as previously described (Yu et al.), all the adherent or all the suspension cell line pools were plated together using T25 flasks (100,000 cells/flask) or 6-well plates (50,000 cells/well), respectively. Cells were treated with either DMSO or compound in a 8-point 3- fold dose response in triplicate, starting from a top concentration of 10 pM. As control for assay robustness, cells were treated in parallel with two previously validated compounds, the pan-Rat inhibitor AZ-628, and the proteasome inhibitor bortezomib, using a top concentration of 2.5 pM and 0.039 pM, respectively.Following 3 days of treatment with compounds, cells were lysed, genomic DNA was extracted, barcodes were amplified by PCR and detected with Next-Generation Sequencing. Cell viability was determined by comparing the counts of cell-line specific barcodes in treated samples to those in the DMSO-control and Day 0 control. Dose-response curves were fit for each cell line and corresponding area under the curves (AUCs) were calculated and compared to the median AUG of all cell lines (FIG. 4). Cell lines with AUCs less than the median were considered most sensitive.
Example 12. Effects of BRG1/BRM ATPase inhibitors on the growth of uveal melanoma cell lines. Procedure: Uveal melanoma cell lines (92-1, MP41, MP38, MP46) and Non-small cell lung cancer cells (NCIH1299) were plated into 96 well plates with growth media (see Table 6). BRG1/BRM ATPase inhibitor, compound 67, was dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Cells were incubated at 37 °C for 3 days. After three days of treatment, cell growth was measured with Cell-titer glow (Promega), and luminescence was read on an Envision plate reader (Perkin Elmer). Results:As shown in FIG. 5, Compound B resulted in potent growth inhibition in the uveal melanoma cell lines.
Example 13. Comparison of BRG1/BRM inhibitors to clinical PKC and MEK inhibitors in uveal melanoma cell lines Procedure:Uveal melanoma cell lines, 92-1 or MP41, were plated in 96 well plates in the presence of growth media (see Table 6). BAF ATPase inhibitor (Compound B), PKC inhibitor (LXS196; MedChemExpress), and MEK inhibitor (Selumetinib; Selleck Chemicals) were dissolved in DMSO and added to the cells in a concentration gradient from 0 to 10 micromolar at the time of plating. Ceils were incubated at 37 °C for 3 days. After three days of treatment, cell growth was measured with Cell-titer glow (Promega), and luminescence was read on an Envision plate reader (Perkin Elmer). Results:As shown in FIG. 6A and FIG. 6B,Compound Bshowed more potent effects on growth inhibition of uveal melanoma cells as compared to the clinical PKC and MEK inhibitors. Further, Compound B was found to result in a faster onset of growth inhibition than the clinical PKC and MEK inhibitors.
Example 14. BRG1/BRM ATPase inhibitors are effective at inhibiting the growth of PKC inhibitor- resistant ceils. Procedure:MP41 uveal melanoma cells were made resistant to the PKC inhibitor (LXS196; MedChemExpress), by long-term culture in growth media (see Table 6) containing increasing 325 WO 2022/103899 PCT/US2021/058865 concentrations of the compound, up to 1 micromoiar. After 3 months, sensitivity of the parental MPcells and the PKC inhibitor (PKCi)-resista nt cells to the PKC inhibitor (LXS196) or the BRG1/BRM ATPase inhibitor (Compound B) was tested in a 7-day growth inhibition assay as described above in Example 9. Results:While the PKCi-resistant cells could tolerate growth at higher concentrations of LXS1than could the parental MP41 cell line (FIG. 7 A), the BRG1/BRM ATPase inhibitor (Compound B) still resulted in strong growth inhibition of both the PKCi-resistant and parental cell lines (FIG. 7B). The PKCi- resistant cells were more sensitive to Compound B than were the parental MP41 cells (FIG. 7B).
Example 15. Synthesis of Compound C 0 (COOhJlMF^ 0 1.TMSCHN2 O vv/ ccm H_/ 2.HCl/d!oxan6 ״. / HO Cl' Ci" A S C MeOH,H2O,NsF HATU.DiEA.DCM HC-l/dioxane ----------------- EDCi,HOBr,DIEA,DCM Compound C Step 1. Preparation of 6-fiuoropyndme-2-carbonyi chloride (Intermediate B) F To a cooled (0 °C) solution of 6-fluoropyridine-2-carboxylic acid (50.00 g, 354.36 mmol) in dichloromethane (500 mb) and N,N-dimethylformamide (0.26 mb, 3.54 mmol) was added oxalyl chloride (155.10 mb, 1.77 mol). After complete addition of oxalyl chloride, the reaction mixture was warmed to room temperature and stirred for an additional 0.5 h. The mixture was concentrated under vacuum to give intermediate B (56.50 g) as a white solid, which was used to next step without further purification.
Step 2. Preparation of 2-chioro-1-(6-fiuoro-2-pyndyi)ethenone (Intermediate C) F ؛- ccTo a cooled (0 °C) mixture of intermediate B (56.00 g, 351.00 mmol) in 1,4-dioxane (800 mb) was added in a dropwise manner a solution of 2 trimethylsilyl diazomethane in hexanes (351 mb). The resulting reaction mixture was stirred at 25 °C for 10 h. The reaction mixture was subsequently quenched with a solution of 4 M HCI in 1,4-dioxane (500 mb). After stirring for 2 h, the reaction solution was concentrated under vacuum to give an oil. The residue was diluted with saturated aqueous NaHCO3 (5mb) and extracted with ethyl acetate (200 mb x 3). The combined organic layers were washed with brine (300 mb x 2), dried over NazSO4, filtered, and concentrated under reduced pressure to give intermediate C (35.50 g) as a white solid, which was used to next step directly. LCMS (ESI) m/z: (M-Hp- 173.8. 326 WO 2022/103899 PCT/US2021/058865 Step 3. Preparation of 4-(6-fiuoro-2-pyr!dyi)th1azoi-2-amme (intermediate E) FH2N N tZAJ ETo a solution of intermediate C (35.50 g, 204.53 mmol) and thiourea (14.01 g, 184.07 mmol) in a mixture of MeOH (250 ml) and H2O (250 ml) at room temperature was added NaF (3.56 g, 84.82 mmol). After stirring for 0.5 h, the reaction mixture was partially concentrated under vacuum to remove MeOH, and the resulting solution was acidified to pH -3 with aqueous 2 M HCI. After 15 min, the solution was extracted with ethyl acetate (200 mL x 3), the organic layers were discarded and the aqueous phase was alkalized with NaHCO3 (500 mL) and stirred for 30 min, then extracted with ethyl acetate (325 mL*3), the combined organic layers were washed with brine (225 mL * 3), dried over N82SO4, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether (300 mL) and stirred at 25 °C for 10 min and filtered. The resultant solids were dried under vacuum to give Intermediate E (28.00 g, 143.43 mmol, 70.13% yield, 100% purity) as a white solid. LCMS (ESI) m/z: [M+H]*= 195.8.; 1H NMR (400 MHz, DMSO-d6) 6 8.00-7.96 (m, 1H), 7.72 (d, J= 7.2 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 2H), 7.02 (d, J= 8.0 Hz, 1H).
Step 4. Preparation of tert-butyl N-[2-[[4-(6-fluoro-2~pyndyl)thiazo8~2-yl]amino]-2-oxo- ethyl]carbamate (Intermediate G) GTo a solution of N-Boc-glycine (5.92 g, 33.81 mmol), HATU (12.86 g, 33.81 mmol), and DIEA (15.89 g, 122.94 mmol, 21.41 mL) in dichloromethane (100 mL) was added intermediate E (6.00 g, 30.74 mmol). After stirring for 2 h, the reaction mixture was concentrated and subsequently diluted with water (100 mL) and extracted with ethyl acetate (60 mL x 4). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with a 1:1 mixture of petroleum ether and MeOH (40mL). After stirring at 25 °C for 20 min, the suspension was filtered, the filter cake was washed with MTBE (20 mL), and dried in vacuo to give Intermediate G (7.7 g, 21.63 mmol, 70.4% yield, 99.0% purity) as a white solid. LCMS (ESI) m/z: [M+Hp = 353.1.
Step 5, Preparation of 2-((4-(6Tfuoropyridin~2-yl)thiaz:oS~2-yl)amirio)-2-oxoethan~1-amm!um chloride (Intermediate H) A solution of Intermediate G (5.40 g, 15.32 mmol) in 4 M HCI in 1,4-dioxane (35 mL) was stirred at 25 °C for 1.5 h. The mixture was concentrated under vacuum to give intermediate H (4.42 g) as a 327 WO 2022/103899 PCT/US2021/058865 white solid, which was used to next, step directly without further purification. LCMS (ESI) m/z: [M+H]+ = 252.9.
Step 6. Preparation of 1-tert-butyi-N-[2-[[4-(6-fiuoro-2-pyridyl)tbiazoi-2-yl]ammo]-2-oxo- ethyl]pyrrole-3-carboxamide (Intermediate J) jTo a solution of intermediate H (3.00 g, 10.39 mmol), 1-tert-butylpyrrole-3-carboxyiic acid (1.g, 10.39 mmol), and DIEA (6.71 g, 51.95 mmol, 9.05 ml) in dichloromethane (40 mL) was sequentially added HOBt (1.68 g, 12.47 mmol) and EDCI (2.39 g, 12.47 mmol). After stirring for 4 h, the mixture was concentrated under vacuum. The residue was diluted with water (250 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting solids were triturated with a 1:1 mixture of MTBE/ethyi acetate (400 mL) and alter 30 min, the suspension was filtered. The solids were washed with MTBE (85 mL x 3) and then dried under vacuum to give intermediate J (3.10 g, 7.mmol, 73.6% yield, 99.0% purity) as a white solid. LCMS (ESI) m/z: [M+Hp = 402.3.1H NMR (400 MHz, DMSO-de) 6 12.40 (s, 1H), 8.18 - 8.15 (m, 1H), 8.09-8.08 (m, 1H), 7.87-7.83 (m, 2H), 7.52 (s, 1H), 7.11 (d, J=8.Q Hz, 1H), 6.97 (m, 1H), 6.47 (s, 1H), 4.10 (d, J=5.6 Hz, 2H), 1.49 (s, 9H).
Step 7. Preparation of 1-(tert-butyi)-N-(2-((4-(6-(cis-2,6-dimethyimorphoiino)pyrid!n-2- yl)thiazol-2-yl)amino)-2-oxoethyi)-1 H-pyrrote-3-carboxamide (Compound C) Vo^ Compaiind CTo a solution of intermediate J (0.100 g, 0.249 mmol) in DMSO (1 mL) was added DIEA (0.1mL, 0.747 mmol) and cis-2,6-dimethylmorpholine (0.057 g, 0.498 mmol) and the mixture was stirred at 120 °C. After 12 h, the solution was cooled to room temperature and reaction mixture was diluted with MeOH (3 mL). The residue was purified by prep-HPLC (0.1% TFA; column: Luna C18 150*25 5u; mobile phase: [water (0.075% TFA) - ACN]; B%: 30%-60%, 2min). The appropriate fractions were collected and lyophilized to give Compound C (0.079 g, 0.129 mmol, 51.94% yield, 100% purity) as a white solid. LCMS (ESI) m/z: [M+Hp = 497.5.1H NMR (400 MHz, DMSO-de) 6 12.27 (s, 1H), 8.17 - 8.14 (m, 1H), 7.75 (s, 1H), 7.63 - 7.59 (m, 1H), 7.(s, 1H),7.25 (d, J = 7.2 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.47 (s, 1H), 4.24 (d, J = 12.4 Hz, 2H), 4.08 (d, J =5.6 Hz, 2H), 3.64 - 3.61 (m, 2H), 2.44 - 2.38 (m, 2H), 1.49 (s, 9H), 1.18 (d, J = 5.6 Hz, 6H). 328 WO 2022/103899 PCT/US2021/058865 Example 16. BRG1/BRM ATPase inhibitors cause uveal melanoma tumor growth Inhibition m vivo. Procedure:Nude mice (Envigo) were engrafted subcutaneously in the axillary region with 5x1 Q92-1 uveal melanoma cells in 50 % Matrigel. Tumors were grown to a mean of -200 mm3, at which point mice were grouped and dosing was initiated. Mice were dosed once daily by oral gavage with vehicle (20% 2-Hydroxypropyl-^-Cyclodextrin) or increasing doses of Compound C. Tumor volumes and body weights were measured over the course of 3 weeks, and doses were adjusted by body weight to achieve the proper dose in terms of mg/kg. At this time, animals were sacrificed, and tumors were dissected and imaged. Results:Treatment with Compound C led to tumor growth inhibition in a dose-dependent manner with tumor regression observed at the highest (50 mg/kg) dose. (FIG. 8A and FIG. 8B). All treatments were well tolerated with no body weight loss observed (FIG. 8C).
Other Embodiments While the invention has been described in connection with specific embodiments thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.Other embodiments are in the claims.

Claims (117)

WO 2022/103899 PCT/US2021/058865 Claims
1. A compound having the structure: Formula I wherein m is 0,1,2, or 3;n is 0, 1,2, 3, or 4;X1 is -S- -SO-, -SO2-, or -S(O)(NH)־;X2 is N or CRS;R1 is hydrogen or optionally substituted C1-C6 alkyl;each R2 and each R3 are independently hydrogen, optionally substituted C1-Cs alkyl, or optionally substituted C:-C5 heteroalkyl;L1 is optionally substituted 9- or 10-membered bicyclic heterocyciyl or optionally substituted 9- or 10-membered bicyclic heteroaryl;L2 is absent, optionally substituted C3-Ci0 cycioalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 14-membered heteroaryl, or optionally substituted 4- to 14-membered heterocyciyl;R4 is hydrogen, halo, optionally substituted C1-C6 alkyl, or optionally substituted C3-C10 cycloalkyl;R5 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted amino, and R6 is hydrogen, halo, cyano, optionally substituted C1-Cb alkyl, optionally substituted C2-C3 alkenyl, or optionally substituted C3-C10 cycioalkyl; or R5 and R6, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 8-membered heterocyciyl;each R7 is independently optionally substituted C1-Ce alkyl, optionally substituted C!-Cs heteroalkyl, halo, optionally substituted C3-C10 cycioalkyl, optionally substituted C3-C10 cycioalkyl C1-Calkyl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted 4- to 14-membered heterocyciyl, -N(R7A)2, or-OR 7A, wherein each R7A is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C3-C10 cycioalkyl, optionally substituted Ce- C10 aryl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 4- to 10-membered heterocyciyl, or two geminal R7A groups, together with the atom to which they are attached, combine to form optionally substituted 5- to 10-membered heteroaryl or optionally substituted 4- to 10-membered heterocyciyl; or two geminal R7 groups, together, with the atom to which they are attached, combine to form carbonyl;R8 is hydrogen, halo, optionally substituted C1-C8 alkyl, or optionally substituted C3-C10 cycioalkyl; andR5 is hydrogen or halo;or a pharmaceutically acceptable salt thereof. 330 WO 2022/103899 PCT/US2021/058865
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 and R6, together with the atoms to which they are attached, combine to form an optionally substituted 5- to 8- membered heterocyclyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 and R6, together with the atoms to which they are attached, combine to form an optionally substituted 7- membered heterocyclyl.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted C1-Cs alkyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted amino.
6. The compound of claim 1,4, or 5, or a pharmaceutically acceptable salt thereof, wherein R6 is optionally substituted C1-C6 alkyl.
7. The compound of claim 1,4, or 5, or a pharmaceutically acceptable salt thereof, wherein R6 is halo.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X1 is SO2.
9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, whereinX2 is CR8.
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a group of the following structure Rs whereinZ is CH2, CO, or C(RX2)2;each RX1 is independently optionally substituted C1-C6 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;each Rx2 is independently H or optionally substituted C1-C6 alkyl; andp is 0, 1,2, 3, or 4. 331 WO 2022/103899 PCT/US2021/058865
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a group of the following structure whereinZ is CH2, CO, or C(RX2)2;each RX1 is independently optionally substituted C؛-C5 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;each Rx2 is independently H or optionally substituted C1-C6 alkyl; andp is 0, 1,2, 3, or 4.
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a group of the following structure >8 whereinZ is CH2, CO, or C(RX2)2;each RX1 is independently optionally substituted C1-C6 alkyl or halo, or two gem/na/RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;each Rx2 is independently hydrogen or optionally substituted C1-C6 alkyl;p is 0, 1,2, 3, or 4; andq is 0 or 1.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a group of the following structure 332 WO 2022/103899 PCT/US2021/058865 wherein؛l is a single bond or double bond;each RX1 is independently optionally substituted C1-C5 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;Rx2 is hydrogen or optionally substituted C1-C8 alkyl; andp is 0, 1,2, 3, or 4.
14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a group of the following structure r8 whereineach RX1 is independently optionally substituted C ؛-C5 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;Rx2 is hydrogen or optionally substituted C1-C8 alkyl; andp is 0, 1,2, 3, or 4.
15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen.
16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R8 is halo.
17. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein X2 is N.
18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein 333 WO 2022/103899 PCT/US2021/058865 is a group of the foliowing structure whereinZ is CH2, CO, or C(RX2)2;each RX1 is independently optionally substituted C1-Cs alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl;each Rx2 is independently hydrogen or optionally substituted C1-C6 alkyl; andp is 0, 1,2, 3, or 4.
19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is a group of the following structure whereineach RX1 is independently optionally substituted C ؛-C5 alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl or Cz-Ca cycloalkyl ring, or two vicinal RX1 groups, together with the atoms to which they are attached, combine to form C3-Ce cycloalkyl ring;p is 0, 1,2, 3, or 4; andq is 0, 1, or 2.
20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is a group of the following structure wherein 334 WO 2022/103899 PCT/US2021/058865 each RX1 is independently optionally substituted C1-Cs alkyl or halo, or two geminal RX1 groups, together with the atom to which they are attached, combine to form a carbonyl; andp is 0, 1,2, 3, or 4.
21. The compound of any one of claims 10 to 14 and 18 to 20, or a pharmaceutically acceptable salt thereof, wherein at least one RX1 is optionally substituted C1-C6 alkyl, or at least one RX1 is halo.
22. The compound of any one of claims 10 to 14 and 18 to 21, or a pharmaceutically acceptable salt thereof, wherein at least two geminal RXi groups, together with the atom to which they are attached, combine to form a carbonyl.
23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein U is optionally substituted 9- or 10-membered bicyclic heteroaryl.
24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein L1 is Formula Awhereineach of X3, X4, X5, X6, X7, and Xs is independently N or CRLi;each RL1 is independently H, halo, optionally substituted C1-C6 alkyl;A1 is a bond to -(C(R2)(R3))m-; andA2 is a bond to L2.
25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein L1 is
26. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein L1 is
27. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein L1 is
28. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein L1 is 335 WO 2022/103899 PCT/US2021/058865
29. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein L1 is
30. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein L؛ is whereinA1 is a bond to ״(C(R2)(R3))m-; andA2 is a bond to L2.
31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein L2 is optionally substituted 5- to 14-membered heteroaryl.
32. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein -L2-(R7)״ is a group of the following structure: 336 WO 2022/103899 PCT/US2021/058865 337 WO 2022/103899 PCT/US2021/058865
33. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein -L2-(R7)fi is a group of the following structure:
34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein -L2-(R')n is a group of the following structure: 338
35.WO 2022/103899 PCT/US2021/058865 35. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein -L2-(R')n is a group of the following structure:
36. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein -L2-(R7)n is a group of the following structure:
37. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein -L2-(R7)n is a group of the following structure:
38. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein -L2-(R7)n is a group of the following structure:
39. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein -L2-(R׳(״ is a group of the following structure: R7
40. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein -L2-(R')n is agroup of the following structure: 339
41.WO 2022/103899 PCT/US2021/058865 41. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein -L2-(R')n is agroup of the following structure:
42. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein L2 is optionally substituted Ce-Ci aryl.
43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein n is 1.
44. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein n is 2.
45. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein n is 3.
46. The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted C1-C6 alkyl.
47. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted C1-C6 heteroalkyl.
48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted 4- to 10-membered heterocyclyi.
49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted azetidinyl or optionally substituted morpholinyL
50. The compound of any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted C3-C10 cycloalkyl.
51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted cyclopropyl or optionally substituted cyclobutyl. 340
52.WO 2022/103899 PCT/US2021/058865 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein R7 is -N(R7A)2.
53. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted N-azetidinyl or optionally substituted N-morpholinyl.
54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein two geminal R7 groups, together with the atom to which they are attached, combine to form optionally substituted 4- to 10-membered heterocyclyl.
55. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, wherein at least one R7 is -OR7A.
56. The compound of claim 52, or a pharmaceutically acceptable salt thereof, wherein R7A is optionally substituted C1-e alkyl.
57. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein n is 0.
58. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, wherein at least one R7 is cyciopropyi, 2,2-difluorocyclopropyi, difluoromethoxy, 2,6-d!methyimorpholin-4- yl, N-azetidinyl, 3-fluorocyciobutyl, 2-methoxyethyi, ethoxy, methoxy, 2,2-difluoroethoxy, 2,2-difluoroethyi, trifluoromethyl, isopropyl, methyl, acetyl, fluoro, chloro, 1-methylpyrazol-3-yl, dimethylamino, N-methyl-N- (2-methoxyethyl)-amino, N-ethyl-N-(2-methoxyethyi)-amino, N-(2-propyl)-N-(2-methoxyethyl)-amino, 2- methoxyethylamino, 3-aza-8-oxa-bicyclo[4.3.0jnon-3-yl, 3-aza-7-oxa-bicydo[4.3.0]non-3-yl, 1- fluorocyclobut-1-yl, 3-fiuoropyrrolid!n-1-yl, 3-methoxypyrrolidin-1-yl, oxetan-3-yl, N-methylindolin-4-yl, 2,2- difluoro-3-methylcycloprop-1-yl, 3-methoxyazetidin-1-yi, 3-methoxypiperidin-1-yl, 1,2-dimethyl-7-azalndoi- 4-yl, 1-methyl-7-azaindol-4-yl, 2,3-methylenedioxyphenyl, N-methyl-N-(3-oxetanyl)amino, 3-oxetanyloxy, 1,1-difiuoro-5-azaspiro[2.3]hex-5-yl, 1-fluoromethyl-cyclopropyl, N-(3-tetrahydrofuranyl)methylamino, N- indolinyl, N-1,4-oxazepanyl, 2-Huoro-2-propyl, 1,1-difluoro-2-propyl, 2,2-difluoro-1-methylcycloprop-1-yl, 1-methylcyclopropyl, 4,4-difluoropiperidin-1-yl, 2-methoxyethoxy, 3,3-difluorocyclobut-1-yl, N-methyl-N-1- methoxyprop-2-ylamino, 1-methoxyprop-2-ylamino, 1-methoxyethyl, 4-methylpiperazinyl, 3- methylmorpholinyl, 2,2-difluoropropoxy, 3-methoxycyclobutyl, methylamino, 4-dimethyiamino-3,3- difluoropiperidinyl, 4-methylamino-3,3-difluoropiperidinyl, 3,3-difluoropyrrolidinyl, N-methyl-N-3- methoxycyclobutylamino, 1-methylpyrazol-5-yl, 6-oxa-3-azabicyclo[3.1.1]hept-3-yl, cyclopropyloxy, 2,6- dimethylpyrid-4-yl, 2-methylpyrrolidinyl, 4-oxabicyclo[4.1.0]hept-1-yl, N-methyi-N-(2,6- dimethyltetrahydropyran-4-yl)amino, or N-methyl-N-3-methyloxetan-3-ylmethylamino.
59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen. 341
60.WO 2022/103899 PCT/US2021/058865 60. A compound selected from the group consisting of compounds 1-308 and pharmaceutically acceptable salts thereof.
61. A compound selected from the group consisting of compounds 309-856 and pharmaceutically acceptable salts thereof.
62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein the compound has a ratio of BRG1 IC50 to BRM IC59 of at least 5.
63. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 7.
64. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein the compound has a ratio of BRG1 IC50 to BRM IC50 of at least 10.
65. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein the compound has a ratio of BRG1 ICs0 to BRM IC50 of at least 15.
66. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein the compound has a ratio of BRG1 ICs0 to BRM IC50 of at least 20.
67. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein the compound has a ratio of BRG1 IC50 to BRM ICs0 of at least 25.
68. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein the compound has a ratio of BRG1 IC50 to BRM ICs0 of at least 30.
69. A pharmaceutical composition comprising a compound of any one of claims 1 to 68 and a pharmaceutically acceptable excipient.
70. A method of decreasing the activity of a BAF complex in a cell, the method comprising contactingthe cell with an effective amount of a compound of any one of claims 1 to 68 or a pharmaceutical composition of claim 69.
71. The method of claim 70, wherein the BAF complex is in a cancer cell.
72. A method of treating a BAF complex-related disorder in a subject in need thereof, the methodcomprising administering to the subject an effective amount of a compound of any one of claims 1 to or a pharmaceutical composition of claim 69.
73. The method of claim 72, wherein the BAF complex-related disorder is cancer or a viral infection. 342
74.WO 2022/103899 PCT/US2021/058865 74. A method of inhibiting BRM, the method comprising contacting a cell with an effective amount of a compound of any one of ciaims 1 to 68 or a pharmaceutical composition of ciaim 69.
75. The method of ciaim 73, wherein the ceil is a cancer cell.
76. A method of treating a disorder related to a BRG1 loss of function mutation in a subject in needthereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 68 ora pharmaceutical composition of claim 69.
77. The method of claim 76, wherein the disorder related to a BRG1 loss of function mutation is cancer.
78. A method of inducing apoptosis in a ceil, the method comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 68 or a pharmaceutical composition of claim 69.
79. The method of claim 78, wherein the cell is a cancer cell.
80. A method of treating cancer in a subject in need thereof, the method comprising administering tothe subject an effective amount of a compound of any one of claims 1 to 68 ora pharmaceutical composition of claim 69.
81. The method of any one of claims 71 to 80, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non- melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin lymphoma, small-cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, Adrenocortical carcinoma, appendiceal cancer, small bowel cancer, or penile cancer.
82. The method of claim 81, wherein the cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, soft tissue sarcoma, or penile cancer.
83. The method of claim 82, wherein the cancer is non-small cell lung cancer.
84. The method of claim 82, wherein the cancer is soft tissue sarcoma.
85. A method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 68 or a pharmaceutical composition of claim 69. 343 WO 2022/103899 PCT/US2021/058865
86. The method of claim 85, wherein the viral infection is an infection with a virus of the Retroviridae family, Hepadnaviridae family, Flaviviridae family, Adenoviridae family, Herpesviridae family, Papillomaviridae family, Parvoviridae family, Polyomaviridae family, Paramyxoviridae family, or Togaviridae family.
87. A method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 68 or a pharmaceutical composition of claim 69.
88. A method of reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 68 or a pharmaceutical composition of claim 69.
89. A method of suppressing metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method comprising administering an effective amount of a compound of any one of claims 1 to 68 or a pharmaceutical composition of claim 69.
90. A method of suppressing metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or a hematologic cancer in a subject, the method comprising administering an effective amount of a compound of any one of claims 1 to 68 or a pharmaceutical composition of claim 69.
91. A method of reducing the level and/or activity of BRG1 and/or BRM in a melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer ceil, the method comprising contacting the cell with an effective amount a compound of any one of claims 1 to 68 or a pharmaceutical composition of claim 69.
92. The method of claim 91, wherein the cell is in a subject.
93. The method of any one of claims 87 to 92, wherein the melanoma, prostate cancer, breastcancer, bone cancer, renal cell carcinoma, or hematologic cancer is metastatic.
94. The method of any one of claims 87 to 92, wherein the method further comprises administering to the subject or contacting the cell with an anticancer therapy.
95. The method of claim 94, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiotherapy, thermotherapy, or photocoagulation, ora combination thereof. 344
96.WO 2022/103899 PCT/US2021/058865 96. The method of claim 95, wherein the anticancer therapy is surgery.
97. The method of claim 95, wherein the anticancer therapy is a chemotherapeutic or cytotoxic agent.
98. The method of claim 97, wherein the chemotherapeutic or cytotoxic agent is an antimetabolite,antimitotic, antitumor antibiotic, asparagine-specific enzyme, bisphosphonates, antineoplastic, alkylating agent, DNA-Repair enzyme inhibitor, histone deacetylase inhibitor, corticosteroid, demethylating agent, immunomodulatory, janus-associated kinase inhibitor, phosphinositide 3-kinase inhibitor, proteasome inhibitor, or tyrosine kinase inhibitor, ora combination thereof.
99. The method of claim 97 or 98, wherein the one or more chemotherapeutic or cytotoxic agent is dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor, a PD-inhibitor, a PD-L1 inhibitor, a mitogen-activated protein kinase inhibitor, and/or a protein kinase C inhibitor.
100. The method of any one of claims 94 to 99, wherein the anticancer therapy and the compound of any one of claims 1 to 38 or a pharmaceutical composition of claim 39 are administered within 28 days of each other and each in an amount that together are effective to treat the subject.
101. The method of any one of claims 87 to 100, wherein the subject or cancer has and/or has been identified as having a BRG1 loss of function mutation.
102. The method of any one of claims 87 to 101, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer has failed to respond to or progressed after administration of one or more chemotherapeutic or cytotoxic agents.
103. The method of any one of claims 87 to 102, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is resistant to, or predicted to be resistant to one or more chemotherapeutic agents.
104. The method of claim 102 or 103, wherein the one or more chemotherapeutic or cytotoxic agents is dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgpWO, a CTLA-4 inhibitor, a PD-inhibitor, a PD-L1 inhibitor, a mitogen-activated protein kinase inhibitor, and/or a protein kinase C inhibitor.
105. The method of any one of claims 87 to 104, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is melanoma.
106. The method of claim 105, wherein the melanoma is uveal melanoma.
107. The method of claim 105, wherein the melanoma is mucosal melanoma. 345
108.WO 2022/103899 PCT/US2021/058865 108. The method of claim 105, wherein the melanoma is cutaneous melanoma.
109. The method of any one of claims 87 to 104, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is a hematologic cancer.
110. The method of claim 109, wherein the hematologic, cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin’s lymphoma.
111. The method of any one of claims 87 to 104, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is prostate cancer.
112. The method of any one of claims 87 to 104, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is breast cancer.
113. The method of claim 112, wherein the breast cancer is an ER positive breast cancer, an ER negative breast cancer, triple positive breast cancer, or triple negative breast cancer.
114. The method of any one of claims 87 to 104, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is bone cancer.
115. The method of claim 114, wherein the bone cancer is Ewing’s sarcoma.
116. The method of any one of claims 87 to 104, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematologic cancer is renal cell carcinoma.
117. The method of claim 116, wherein the renal cell carcinoma is Microphthalmia Transcription Factor (MITF) family translocation renal cell carcinoma. 346
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